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Wang J, Li S, Ye J, Yan Y, Liu Q, Jia Q, Jia Y, Wang L. Mesencephalic astrocyte-derived neurotrophic factor (MANF): A novel therapeutic target for chemotherapy-induced peripheral neuropathy via regulation of integrated stress response and neuroinflammation. Neuropharmacology 2025; 268:110342. [PMID: 39909174 DOI: 10.1016/j.neuropharm.2025.110342] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2024] [Revised: 01/20/2025] [Accepted: 02/01/2025] [Indexed: 02/07/2025]
Abstract
Chemotherapy-induced peripheral neuropathy (CIPN) represents a severe complication, impacting up to 90% of cancer patients administered with chemotherapeutic agents such as oxaliplatin. The purpose of our study was to examine the potential role and therapeutic efficacy of Mesencephalic Astrocyte-derived Neurotrophic Factor (MANF), given its recognized neuroprotective and immunomodulatory properties in diverse neurological disorders. Utilizing an oxaliplatin-induced CIPN mouse model, we investigated MANF expression in the dorsal root ganglia (DRG) and spinal cord, and evaluated the impacts of AAV-mediated MANF overexpression on CIPN. Our findings revealed substantial downregulation of MANF expression in both the DRG and spinal cord of CIPN inflicted mice, with MANF majorly localized in neurons as opposed to glial cells. Intrathecal administration of AAV-MANF preceding oxaliplatin treatment yielded several beneficial results. MANF overexpression diminished mechanical hypersensitivity and decreased Calcitonin Gene-Related Peptide (CGRP) expression in DRG and the spinal dorsal horn. These enhancements were concomitant with modulation of the integrated stress response (ISR) and neuroinflammation. Intervention with AAV-MANF effectively regulated ISR markers (BiP, CHOP, and p-eIF2α), mitigated activation of microglia and astrocytes in the DRG and spinal dorsal horn, and inhibited NFκB and ERK inflammatory signaling pathways. To conclude, our study underscores the potential of MANF as a viable therapeutic target for CIPN, manifesting its ability to modulate ISR and neuroinflammation. These insights recommend that continued exploration of MANF-centered approaches could facilitate the advancement of more efficacious interventions for this incapacitating chemotherapy complication.
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Affiliation(s)
- Juan Wang
- Department of Pain, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei Province, China
| | - Shenghong Li
- Department of Pain, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei Province, China
| | - Jishi Ye
- Department of Pain, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei Province, China
| | - Yafei Yan
- Department of Pain, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei Province, China
| | - Qi Liu
- Department of Pain, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei Province, China
| | - Qiang Jia
- Department of Pain, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei Province, China
| | - Yifan Jia
- Department of Pain, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei Province, China.
| | - Long Wang
- Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei Province, China.
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Dai P, Wang P, Chen X, Feng S, Wu F, Zheng X, Qin Z. Mesencephalic Astrocyte-Derived Neurotrophic Factor (MANF) Restricts Inflammatory Progression through Limiting Macrophage Infiltration in DRG and Sciatic Nerve during Diabetic Peripheral Neuropathy. ACS Chem Neurosci 2025; 16:945-959. [PMID: 39970444 DOI: 10.1021/acschemneuro.5c00021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/21/2025] Open
Abstract
Diabetic peripheral neuropathy (DPN) is a prevalent complication affecting over half of individuals with diabetes. This study investigates the role of mesencephalic Astrocyte-derived neurotrophic factor (MANF) in DPN progression and its potential as a therapeutic target. Using a streptozotocin (STZ)-induced diabetic mouse model, we analyzed MANF expression in the dorsal root ganglia (DRG) and sciatic nerve and assessed the effects of recombinant human MANF (rhMANF) administration on DPN symptoms. Our findings show significant upregulation of MANF protein levels in the DRG of diabetic mice, along with an increased presence of MANF-expressing macrophages in both the DRG and sciatic nerve. Intravenous administration of rhMANF from Day 7 to Day 21 post-STZ injection yielded multiple beneficial outcomes. Notably, rhMANF treatment alleviated mechanical hypoalgesia, as measured by the paw mechanical withdrawal threshold (PMWT), and enhanced sciatic nerve conduction, improving motor nerve conduction velocity (MNCV). Additionally, it increased intradermal nerve density, indicated by more PGP9.5-positive nerve fibers in the plantar skin of treated diabetic mice. These improvements were associated with reduced macrophage infiltration in the DRG and sciatic nerve, marked by fewer CD68 and Iba-1 positive cells, and inhibition of inflammatory signaling pathways. Specifically, rhMANF treatment decreased NF-κB p65 phosphorylation and suppressed p38 MAPK phosphorylation, indicating reduced inflammation. In summary, our research underscores MANF's potential as a novel therapeutic target for DPN, particularly due to its anti-inflammatory properties. Further exploration of MANF could lead to the development of more effective treatments for this debilitating aspect of diabetes.
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Affiliation(s)
- Peng Dai
- Department of Anesthesiology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P. R. China
- Department of Anesthesiology, The First People's Hospital of Foshan, Foshan, Guangdong 528000, P. R. China
| | - Peng Wang
- Department of Anesthesiology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P. R. China
| | - Xin Chen
- Department of Anesthesiology, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi 710068, P. R. China
| | - Shuyun Feng
- Department of Anesthesiology, The First People's Hospital of Foshan, Foshan, Guangdong 528000, P. R. China
| | - Fancan Wu
- Department of Anesthesiology, The First People's Hospital of Foshan, Foshan, Guangdong 528000, P. R. China
| | - Xueqin Zheng
- Department of Anesthesiology, The First People's Hospital of Foshan, Foshan, Guangdong 528000, P. R. China
| | - Zaisheng Qin
- Department of Anesthesiology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P. R. China
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Ge K, Bai Z, Wang J, Li Z, Gao F, Liu S, Zhang L, Gao F, Xie C. Engineering EVs-Mediated mRNA Delivery Regulates Microglia Function and Alleviates Depressive-Like Behaviors. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2025; 37:e2418872. [PMID: 39838773 DOI: 10.1002/adma.202418872] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/03/2024] [Revised: 01/13/2025] [Indexed: 01/23/2025]
Abstract
The development of new non-neurotransmitter drugs is an important supplement to the clinical treatment of major depressive disorder. The latest development of mRNA therapy provides the possibility for the treatment of some major diseases. The endoplasmic reticulum (ER) and mitochondria constitute a highly interconnected set of fundamental organelles within cells. The interconnection between them forms specific microdomains that play pivotal roles in calcium signaling, mitochondrial dynamics, inflammation, and autophagy. Perturbations in ER-mitochondrial connections may contribute to the progression of neurological disorders and other diseases. Herein, an extracellular vesicles-based delivery system, grounded in mRNA gene therapy and integrated with nanomedicine technology is devised. This system is engineered to traverse the blood-brain barrier and specifically target the central nervous system (CNS), facilitating the simultaneous delivery of mRNA drugs and metallic nanozymes into the brain. This dual-pronged approach, targeting ER and mitochondrial crosstalk, inhibits microglial overactivation, promotes M2 polarization of microglia, and suppresses the NF-κB signaling pathway. Consequently, it significantly alleviates Lipopolysaccharides-induced neuroinflammatory responses and ameliorates anxiety- and depression-like behaviors. This study demonstrates a novel antidepressant therapeutic strategy and establishes a new paradigm for mRNA gene therapy in CNS diseases.
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Affiliation(s)
- Kezhen Ge
- Department of Neurology, Affiliated ZhongDa Hospital, School of Medicine, Southeast University, Jiangsu, 210009, P. R. China
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Jiangsu, 221002, P. R. China
| | - Zetai Bai
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Jiangsu, 221002, P. R. China
| | - Jiwei Wang
- Department of Neurology, Affiliated ZhongDa Hospital, School of Medicine, Southeast University, Jiangsu, 210009, P. R. China
| | - Zheng Li
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Jiangsu, 221002, P. R. China
| | - Fenfang Gao
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Jiangsu, 221002, P. R. China
| | - Sangni Liu
- Department of Neurology, Affiliated ZhongDa Hospital, School of Medicine, Southeast University, Jiangsu, 210009, P. R. China
| | - Ling Zhang
- Department of Neurology, Affiliated ZhongDa Hospital, School of Medicine, Southeast University, Jiangsu, 210009, P. R. China
| | - Fenglei Gao
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Jiangsu, 221002, P. R. China
| | - Chunming Xie
- Department of Neurology, Affiliated ZhongDa Hospital, School of Medicine, Southeast University, Jiangsu, 210009, P. R. China
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Xiong Z, Yang L, Zhang C, Huang W, Zhong W, Yi J, Feng J, Zouxu X, Song L, Wang X. MANF facilitates breast cancer cell survival under glucose-starvation conditions via PRKN-mediated mitophagy regulation. Autophagy 2025; 21:80-101. [PMID: 39147386 DOI: 10.1080/15548627.2024.2392415] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Revised: 08/05/2024] [Accepted: 08/11/2024] [Indexed: 08/17/2024] Open
Abstract
During tumor expansion, breast cancer (BC) cells often experience reactive oxygen species accumulation and mitochondrial damage because of glucose shortage. However, the mechanism by which BC cells deal with the glucose-shortage-induced oxidative stress remains unclear. Here, we showed that MANF (mesencephalic astrocyte derived neurotrophic factor)-mediated mitophagy facilitates BC cell survival under glucose-starvation conditions. MANF-mediated mitophagy also promotes fatty acid oxidation in glucose-starved BC cells. Moreover, during glucose starvation, SENP1-mediated de-SUMOylation of MANF increases cytoplasmic MANF expression through the inhibition of MANF's nuclear translocation and hence renders mitochondrial distribution of MANF. MANF mediates mitophagy by binding to PRKN (parkin RBR E3 ubiquitin protein ligase), a key mitophagy regulator, in the mitochondria. Under conditions of glucose starvation, protein oxidation inhibits PRKN activity; nevertheless, the CXXC motif of MANF alleviates protein oxidation in RING II-domain of PRKN and restores its E3 ligase activity. Furthermore, MANF-PRKN interactions are essential for BC tumor growth and metastasis. High MANF expression predicts poor outcomes in patients with BC. Our results highlight the prosurvival role of MANF-mediated mitophagy in BC cells during glucose starvation, suggesting MANF as a potential therapeutic target.Abbreviation: 2DG, 2-deoxy-D-glucose; 5TG, 5-thio-D-glucose; ACSL4/FACL4, acyl-CoA synthetase long chain family member 4; Baf A1, bafilomycin A1; BRCA, breast cancer; CHX, cycloheximide; DMF, distant metastasis-free; DMFS, distant metastasis-free survival; ECM, extracellular matrix; ER, endoplasmic reticulum; ERS, endoplasmic reticulum stress; F-1,6-BP, fructose-1,6-bisphosphate; FAO, fatty acid oxidation; GSH, reduced glutathione; GSVA, gene set variation analysis; HCC, hepatocellular carcinoma; ICC, intrahepatic cholangiocarcinoma; IF, immunofluorescence; MANF, mesencephalic astrocyte derived neurotrophic factor; Mdivi-1, mitochondrial division inhibitor 1; MFI, mean fluorescence intensity; NAC, N-acetyl-L-cysteine; OCR, oxygen-consumption rate; OS, overall survival; PMI, SQSTM1/p62-mediated mitophagy inducer; PPP, pentose phosphate pathway; PRKN, parkin RBR E3 ubiquitin protein ligase; RBR, RING in between RING; RFS, relapse-free survival; ROS, reactive oxygen species; SAPLIPs, saposin-like proteins; TCGA, The Cancer Genome Atlas; TNBC, triple-negative breast cancer; WT, wild type.
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Affiliation(s)
- Zhenchong Xiong
- Department of Breast Oncology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Lin Yang
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Chao Zhang
- Department of Breast Oncology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Weiling Huang
- Department of Breast Oncology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Wenjing Zhong
- Department of Breast Oncology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Jiarong Yi
- Department of Breast Oncology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Jikun Feng
- Department of Breast Oncology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Xiazi Zouxu
- Department of Breast Oncology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Libing Song
- Department of Experimental Research, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
- Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Institute of Oncology, Tumor Hospital, Guangzhou Medical University, Guangzhou, China
| | - Xi Wang
- Department of Breast Oncology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
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Running L, Cristobal JR, Karageorgiou C, Camdzic M, Aguilar JMN, Gokcumen O, Aga DS, Atilla-Gokcumen GE. Investigating the Mechanism of Neurotoxic Effects of PFAS in Differentiated Neuronal Cells through Transcriptomics and Lipidomics Analysis. ACS Chem Neurosci 2024; 15:4568-4579. [PMID: 39603830 DOI: 10.1021/acschemneuro.4c00652] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2024] Open
Abstract
Per- and polyfluorinated alkyl substances (PFAS) are pervasive environmental contaminants that bioaccumulate in tissues and pose risks to human health. Increasing evidence links PFAS to neurodegenerative and behavioral disorders, yet the underlying mechanisms of their effects on neuronal function remain largely unexplored. In this study, we utilized SH-SY5Y neuroblastoma cells, differentiated into neuronal-like cells, to investigate the impact of six PFAS compounds─perfluorooctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS), perfluorodecanoic acid (PFDA), perfluorodecanesulfonic acid (PFDS), 8:2 fluorotelomer sulfonate (8:2 FTS), and 8:2 fluorotelomer alcohol (8:2 FTOH)─on neuronal health. Following a 30 μM exposure for 24 h, PFAS accumulation ranged from 40-6500 ng/mg of protein. Transcriptomic analysis revealed 721 differentially expressed genes (DEGs) across treatments (padj < 0.05), with 11 DEGs shared among all PFAS exposures, indicating potential biomarkers for neuronal PFAS toxicity. PFOA-treated cells showed downregulation of genes involved in synaptic growth and neural function, while PFOS, PFDS, 8:2 FTS, and 8:2 FTOH exposures resulted in the upregulation of genes related to hypoxia response and amino acid metabolism. Lipidomic profiling further demonstrated significant increases in fatty acid levels with PFDA, PFDS, and 8:2 FTS and depletion of triacylglycerols with 8:2 FTOH treatments. These findings suggest that the neurotoxic effects of PFAS are structurally dependent, offering insights into the molecular processes that may drive PFAS-induced neuronal dysfunction.
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Affiliation(s)
- Logan Running
- Department of Chemistry, University at Buffalo, The State University of New York (SUNY), Buffalo, New York 14260, United States
| | - Judith R Cristobal
- Department of Chemistry, University at Buffalo, The State University of New York (SUNY), Buffalo, New York 14260, United States
- RENEW Institute, University at Buffalo, The State University of New York (SUNY), Buffalo, New York 14260, United States
| | - Charikleia Karageorgiou
- Department of Biological Sciences, University at Buffalo, The State University of New York (SUNY), Buffalo, New York 14260, United States
| | - Michelle Camdzic
- Department of Chemistry, University at Buffalo, The State University of New York (SUNY), Buffalo, New York 14260, United States
| | - John Michael N Aguilar
- Department of Chemistry, University at Buffalo, The State University of New York (SUNY), Buffalo, New York 14260, United States
| | - Omer Gokcumen
- Department of Biological Sciences, University at Buffalo, The State University of New York (SUNY), Buffalo, New York 14260, United States
| | - Diana S Aga
- Department of Chemistry, University at Buffalo, The State University of New York (SUNY), Buffalo, New York 14260, United States
- RENEW Institute, University at Buffalo, The State University of New York (SUNY), Buffalo, New York 14260, United States
| | - G Ekin Atilla-Gokcumen
- Department of Chemistry, University at Buffalo, The State University of New York (SUNY), Buffalo, New York 14260, United States
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Shen Y, Wang J, Liang J, Chen Y, Wu X, Ren Z, Zhou J, Feng L, Shen Y. E3 Ubiquitin Ligase Ring Finger Protein 2 Alleviates Cerebral Ischemia-Reperfusion Injury by Stabilizing Mesencephalic Astrocyte-Derived Neurotrophic Factor Through Monoubiquitination. CNS Neurosci Ther 2024; 30:e70136. [PMID: 39614674 DOI: 10.1111/cns.70136] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2024] [Revised: 10/18/2024] [Accepted: 11/12/2024] [Indexed: 12/01/2024] Open
Abstract
AIM Cerebral ischemic stroke (IS) is one of the leading causes of morbidity and mortality globally. However, the mechanisms underlying IS injury remain poorly understood. Ring finger protein 2 (RNF2), the member of the polycomb family (PcG), has been implicated in diverse biological and pathological conditions. However, whether RNF2 plays a role in IS progression is not clarified. This study aims to investigate the potential effects of RNF2 on IS. METHODS The effects of RNF2 were studied in human postmortem IS brains, a rat model of IS, tunicamycin (TM)-induced mouse neuroblastoma neuro2a (N2a) cells, and oxygen-glucose deprivation/reperfusion (OGD/R)-induced SH-SY5Y cells. RESULTS Here, we demonstrated that RNF2 was markedly upregulated both in human postmortem IS brains and ischemic rat brains and RNF2 overexpression alleviated brain injury induced by middle cerebral artery occlusion by reducing neuron apoptosis. Mechanistically, we found that RNF2 is an E3 ubiquitin ligase for the mesencephalic astrocyte-derived neurotrophic factor (MANF), which confers protection against brain ischemia. RNF2 interacted with MANF and promoted the monoubiquitination of MANF, consequently facilitating its stability and nuclear localization. CONCLUSION Collectively, RNF2 is identified as a critical inhibitor of IS injury by stabilizing MANF through monoubiquitination, suggesting that RNF2 is a potential therapeutic target for IS.
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Affiliation(s)
- Yujun Shen
- School of Basic Medical Sciences, Anhui Medical University, Hefei, China
- Biopharmaceutical Research Institute, Anhui Medical University, Hefei, China
| | - Jinfeng Wang
- School of Basic Medical Sciences, Anhui Medical University, Hefei, China
- Biopharmaceutical Research Institute, Anhui Medical University, Hefei, China
| | - Junxing Liang
- School of Basic Medical Sciences, Anhui Medical University, Hefei, China
- Biopharmaceutical Research Institute, Anhui Medical University, Hefei, China
| | - Ying Chen
- School of Basic Medical Sciences, Anhui Medical University, Hefei, China
- Biopharmaceutical Research Institute, Anhui Medical University, Hefei, China
| | - Xueyan Wu
- School of Basic Medical Sciences, Anhui Medical University, Hefei, China
- Anhui Provincial Key Laboratory for Brain Bank Construction and Resource Utilization, Anhui Medical University, Hefei, China
| | - Zhenhua Ren
- School of Basic Medical Sciences, Anhui Medical University, Hefei, China
- Anhui Provincial Key Laboratory for Brain Bank Construction and Resource Utilization, Anhui Medical University, Hefei, China
| | - Jiangning Zhou
- Anhui Provincial Key Laboratory for Brain Bank Construction and Resource Utilization, Anhui Medical University, Hefei, China
| | - Lijie Feng
- School of Basic Medical Sciences, Anhui Medical University, Hefei, China
- Biopharmaceutical Research Institute, Anhui Medical University, Hefei, China
- Anhui Provincial Key Laboratory for Brain Bank Construction and Resource Utilization, Anhui Medical University, Hefei, China
| | - Yuxian Shen
- School of Basic Medical Sciences, Anhui Medical University, Hefei, China
- Biopharmaceutical Research Institute, Anhui Medical University, Hefei, China
- Anhui Provincial Key Laboratory for Brain Bank Construction and Resource Utilization, Anhui Medical University, Hefei, China
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Zhang Y, Chen X, Chen L, Shao M, Zhu W, Xing T, Guo T, Jia Q, Yang H, Yin P, Yan XX, Yu J, Li S, Li XJ, Yang S. Increased expression of mesencephalic astrocyte-derived neurotrophic factor (MANF) contributes to synapse loss in Alzheimer's disease. Mol Neurodegener 2024; 19:75. [PMID: 39425207 PMCID: PMC11490049 DOI: 10.1186/s13024-024-00771-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2024] [Accepted: 10/11/2024] [Indexed: 10/21/2024] Open
Abstract
BACKGROUND The activation of endoplasmic reticulum (ER) stress is an early pathological hallmark of Alzheimer's disease (AD) brain, but how ER stress contributes to the onset and development of AD remains poorly characterized. Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a non-canonical neurotrophic factor and an ER stress inducible protein. Previous studies reported that MANF is increased in the brains of both pre-symptomatic and symptomatic AD patients, but the consequence of the early rise in MANF protein is unknown. METHODS We examined the expression of MANF in the brain of AD mouse models at different pathological stages. Through behavioral, electrophysiological, and neuropathological analyses, we assessed the level of synaptic dysfunctions in the MANF transgenic mouse model which overexpresses MANF in the brain and in wild type (WT) mice with MANF overexpression in the hippocampus. Using proteomic and transcriptomic screening, we identified and validated the molecular mechanism underlying the effects of MANF on synaptic function. RESULTS We found that increased expression of MANF correlates with synapse loss in the hippocampus of AD mice. The ectopic expression of MANF in mice via transgenic or viral approaches causes synapse loss and defects in learning and memory. We also identified that MANF interacts with ELAV like RNA-binding protein 2 (ELAVL2) and affects its binding to RNA transcripts that are involved in synaptic functions. Increasing or decreasing MANF expression in the hippocampus of AD mice exacerbates or ameliorates the behavioral deficits and synaptic pathology, respectively. CONCLUSIONS Our study established MANF as a mechanistic link between ER stress and synapse loss in AD and hinted at MANF as a therapeutic target in AD treatment.
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Affiliation(s)
- Yiran Zhang
- Guangdong Key Laboratory of Non-Human Primate Research, Key Laboratory of CNS Regeneration (Ministry of Education), Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, China
| | - Xiusheng Chen
- Guangdong Key Laboratory of Non-Human Primate Research, Key Laboratory of CNS Regeneration (Ministry of Education), Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, China
| | - Laiqiang Chen
- Guangdong Key Laboratory of Non-Human Primate Research, Key Laboratory of CNS Regeneration (Ministry of Education), Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, China
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou, China
| | - Mingting Shao
- Guangdong Key Laboratory of Non-Human Primate Research, Key Laboratory of CNS Regeneration (Ministry of Education), Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, China
| | - Wenzhen Zhu
- Guangdong Key Laboratory of Non-Human Primate Research, Key Laboratory of CNS Regeneration (Ministry of Education), Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, China
| | - Tingting Xing
- Guangdong Key Laboratory of Non-Human Primate Research, Key Laboratory of CNS Regeneration (Ministry of Education), Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, China
| | - Tingting Guo
- Guangdong Key Laboratory of Non-Human Primate Research, Key Laboratory of CNS Regeneration (Ministry of Education), Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, China
| | - Qingqing Jia
- Guangdong Key Laboratory of Non-Human Primate Research, Key Laboratory of CNS Regeneration (Ministry of Education), Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, China
| | - Huiming Yang
- Department of Neurology, The First Affiliated Hospital, Sun Yat-Sen University; Guangdong Provincial Key Laboratory of Diagnosis and Treatment of Major Neurological Diseases, Guangzhou, China
| | - Peng Yin
- Guangdong Key Laboratory of Non-Human Primate Research, Key Laboratory of CNS Regeneration (Ministry of Education), Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, China
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou, China
| | - Xiao-Xin Yan
- Department of Anatomy and Neurobiology, Central South University Xiangya School of Medicine, Changsha, China
| | - Jiandong Yu
- Department of Neurosurgery, The First Affiliated Hospital of Bengbu Medical College, Bengbu, China
| | - Shihua Li
- Guangdong Key Laboratory of Non-Human Primate Research, Key Laboratory of CNS Regeneration (Ministry of Education), Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, China
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou, China
| | - Xiao-Jiang Li
- Guangdong Key Laboratory of Non-Human Primate Research, Key Laboratory of CNS Regeneration (Ministry of Education), Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, China
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou, China
| | - Su Yang
- Guangdong Key Laboratory of Non-Human Primate Research, Key Laboratory of CNS Regeneration (Ministry of Education), Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, China.
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou, China.
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8
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Lõhelaid H, Saarma M, Airavaara M. CDNF and ER stress: Pharmacology and therapeutic possibilities. Pharmacol Ther 2024; 254:108594. [PMID: 38290651 DOI: 10.1016/j.pharmthera.2024.108594] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2023] [Revised: 12/28/2023] [Accepted: 01/18/2024] [Indexed: 02/01/2024]
Abstract
Cerebral dopamine neurotrophic factor (CDNF) is an endogenous protein in humans and other vertebrates, and it has been shown to have protective and restorative effects on cells in various disease models. Although it is named as a neurotrophic factor, its actions are drastically different from classical neurotrophic factors such as neurotrophins or the glial cell line-derived neurotrophic family of proteins. Like all secreted proteins, CDNF has a signal sequence at the N-terminus, but unlike common growth factors it has a KDEL-receptor retrieval sequence at the C-terminus. Thus, CDNF is mainly located in the ER. In response to adverse effects, such as ER stress, the expression of CDNF is upregulated and can alleviate ER stress. Also different from other neurotrophic factors, CDNF reduces protein aggregation and inflammation in disease models. Although it is an ER luminal protein, it can surprisingly directly interact with alpha-synuclein, a protein involved in the pathogenesis of synucleinopathies e.g., Parkinson's disease. Pleiotropic CDNF has therapeutic potential and has been tested as a recombinant human protein and gene therapy. The neuroprotective and neurorestorative effects have been described in a number of preclinical studies of Parkinson's disease, stroke and amyotrophic lateral sclerosis. Currently, it was successfully evaluated for safety in a phase 1/2 clinical trial for Parkinson's disease. Collectively, based on recent findings on the mode of action and therapeutic potential of CDNF, its use as a drug could be expanded to other ER stress-related diseases.
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Affiliation(s)
- Helike Lõhelaid
- Drug Research Program, Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, University of Helsinki, Finland; Neuroscience Center, Helsinki Institute of Life Science, University of Helsinki, Finland
| | - Mart Saarma
- Institute of Biotechnology, Helsinki Institute of Life Science, University of Helsinki, Finland
| | - Mikko Airavaara
- Drug Research Program, Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, University of Helsinki, Finland; Neuroscience Center, Helsinki Institute of Life Science, University of Helsinki, Finland.
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9
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Liu H, Dong H, Wang C, Jia W, Wang G, Wang H, Zhong L, Gong L. Key Subdomains of Cerebral Dopamine Neurotrophic Factor Regulate Its Protective Function in 6-Hydroxydopamine-Lesioned PC12 Cells. DNA Cell Biol 2023; 42:680-688. [PMID: 37815547 PMCID: PMC10663698 DOI: 10.1089/dna.2023.0215] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2023] [Revised: 08/22/2023] [Accepted: 08/23/2023] [Indexed: 10/11/2023] Open
Abstract
Cerebral dopamine neurotrophic factor (CDNF) is a unique neurotrophic factor (NTF) that has shown significant neuroprotective and neurorestorative functions on midbrain dopaminergic neurons. The secondary structure of human CDNF protein contains eight α-helices. We previously found that two key helices, α1 and α7, regulated the intracellular trafficking and secretion of CDNF protein in different manners. The α1 mutation (M1) induced most CDNF proteins to reside in the endoplasmic reticulum and little be secreted extracellularly, while the α7 mutation (M7) caused the majority of CDNF proteins to be secreted out of the cells and little reside in the cells. However, the regulation of the two mutants on the function of CDNF remains unclear. In this study, we investigated the effects of M1 and M7 on the protective activity of CDNF in PC12 cells, which were treated with 6-hydroxydopamine (6-OHDA) to mimic Parkinson's disease. We found that both M1 and M7 could promote survival and inhibit apoptosis more effectively than Wt in 6-OHDA-lesioned PC12 cells. Therefore, these findings will advance our understanding of the important regulation of subdomains on the function of NTFs.
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Affiliation(s)
- Hao Liu
- The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, China
| | - Haibin Dong
- The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, China
| | - Chunxiao Wang
- The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, China
| | - Wenjuan Jia
- The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, China
| | - Guangqiang Wang
- The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, China
| | - Hua Wang
- The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, China
| | - Lin Zhong
- The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, China
| | - Lei Gong
- The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, China
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10
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Wen W, Wang Y, Li H, Hu D, Zhang Z, Lin H, Luo J. Upregulation of mesencephalic astrocyte-derived neurotrophic factor (MANF) expression offers protection against alcohol neurotoxicity. J Neurochem 2023; 166:943-959. [PMID: 37507360 PMCID: PMC10906989 DOI: 10.1111/jnc.15921] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Revised: 07/05/2023] [Accepted: 07/06/2023] [Indexed: 07/30/2023]
Abstract
Alcohol exposure has detrimental effects on both the developing and mature brain. Endoplasmic reticulum (ER) stress is one of the mechanisms that contributes to alcohol-induced neuronal damages. Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an ER stress-responsive protein and is neuroprotective in multiple neuronal injury and neurodegenerative disease models. MANF deficiency has been shown to exacerbate alcohol-induced ER stress and neurodegeneration. However, it is unknown whether MANF supplement is sufficient to protect against alcohol neurotoxicity. Alcohol alters MANF expression in the brain, but the mechanisms underlying alcohol modulation of MANF expression remain unclear. This study was designed to determine how alcohol alters MANF expression in neuronal cells and whether exogeneous MANF can alleviate alcohol neurotoxicity. We showed that alcohol increased MANF transcription and secretion without affecting MANF mRNA stability and protein degradation. ER stress was necessary for alcohol-induced MANF upregulation, as pharmacological inhibition of ER stress by 4-PBA diminished alcohol-induced MANF expression. In addition, the presence of ER stress response element II (ERSE-II) was required for alcohol-stimulated MANF transcription. Mutations or deletion of this sequence abolished alcohol-regulated transcriptional activity. We generated MANF knockout (KO) neuronal cells using CRISPR/Cas9. MANF KO cells exhibited increased unfolded protein response (UPR) and were more susceptible to alcohol-induced cell death. On the other hand, MANF upregulation by the addition of recombinant MANF protein or adenovirus gene transduction protected neuronal cells against alcohol-induced cell death. Further studies using early postnatal mouse pups demonstrated that enhanced MANF expression in the brain by intracerebroventricular (ICV) injection of MANF adeno-associated viruses ameliorated alcohol-induced cell death. Thus, alcohol increased MANF expression through inducing ER stress, which could be a protective response. Exogenous MANF was able to protect against alcohol-induced neurodegeneration.
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Affiliation(s)
- Wen Wen
- Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
| | - Yongchao Wang
- Vanderbilt Memory and Alzheimer’s Center, Department of Neurology, Vanderbilt University Medical Center, Nashville, TN 37372, USA
| | - Hui Li
- Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
| | - Di Hu
- Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
| | - Zuohui Zhang
- Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
| | - Hong Lin
- Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
| | - Jia Luo
- Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
- VA Iowa City Health Care System, Iowa City, IA 52246, USA
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11
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Pakarinen E, Lindholm P. CDNF and MANF in the brain dopamine system and their potential as treatment for Parkinson's disease. Front Psychiatry 2023; 14:1188697. [PMID: 37555005 PMCID: PMC10405524 DOI: 10.3389/fpsyt.2023.1188697] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Accepted: 05/23/2023] [Indexed: 08/10/2023] Open
Abstract
Parkinson's disease (PD) is a progressive neurodegenerative disease characterized by gradual loss of midbrain dopamine neurons, leading to impaired motor function. Preclinical studies have indicated cerebral dopamine neurotrophic factor (CDNF) and mesencephalic astrocyte-derived neurotrophic factor (MANF) to be potential therapeutic molecules for the treatment of PD. CDNF was proven to be safe and well tolerated when tested in Phase I-II clinical trials in PD patients. Neuroprotective and neurorestorative effects of CDNF and MANF were demonstrated in animal models of PD, where they promoted the survival of dopamine neurons and improved motor function. However, biological roles of endogenous CDNF and MANF proteins in the midbrain dopamine system have been less clear. In addition to extracellular trophic activities, CDNF/MANF proteins function intracellularly in the endoplasmic reticulum (ER), where they modulate protein homeostasis and protect cells against ER stress by regulating the unfolded protein response (UPR). Here, our aim is to give an overview of the biology of endogenous CDNF and MANF in the brain dopamine system. We will discuss recent studies on CDNF and MANF knockout animal models, and effects of CDNF and MANF in preclinical models of PD. To elucidate possible roles of CDNF and MANF in human biology, we will review CDNF and MANF tissue expression patterns and regulation of CDNF/MANF levels in human diseases. Finally, we will discuss novel findings related to the molecular mechanism of CDNF and MANF action in ER stress, UPR, and inflammation, all of which are mechanisms potentially involved in the pathophysiology of PD.
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Affiliation(s)
| | - Päivi Lindholm
- Institute of Biotechnology, Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland
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12
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Sivakumar B, Krishnan A. Mesencephalic Astrocyte-Derived Neurotrophic Factor (MANF): An Emerging Therapeutic Target for Neurodegenerative Disorders. Cells 2023; 12:cells12071032. [PMID: 37048105 PMCID: PMC10093115 DOI: 10.3390/cells12071032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 03/12/2023] [Accepted: 03/26/2023] [Indexed: 03/30/2023] Open
Abstract
Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a member of the new family of neurotrophic factors (NTFs) with a unique structure and functions compared to other conventionally known NTFs. MANF is broadly expressed in developing and mature tissues, including the central nervous system and peripheral nervous system tissues. Growing research demonstrated that MANF protects neurons from endoplasmic reticulum (ER) stress-associated complications by restoring ER homeostasis and regulating unfolded protein response. This review discusses MANF signaling in neurodegenerative conditions with specific emphasis given to its overall effect and mechanisms of action in experimental models of Parkinson’s disease, Alzheimer’s disease, and stroke. Additional perspectives on its potential unexplored roles in other neurodegenerative conditions are also given.
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Affiliation(s)
- Bhadrapriya Sivakumar
- Department of Anatomy, Physiology, and Pharmacology, College of Medicine, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada
- Cameco MS Neuroscience Research Centre (CMSNRC), Saskatoon, SK S7K 0M7, Canada
| | - Anand Krishnan
- Department of Anatomy, Physiology, and Pharmacology, College of Medicine, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada
- Cameco MS Neuroscience Research Centre (CMSNRC), Saskatoon, SK S7K 0M7, Canada
- Correspondence: ; Tel.: +1-306-655-8711
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13
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Kovaleva V, Yu LY, Ivanova L, Shpironok O, Nam J, Eesmaa A, Kumpula EP, Sakson S, Toots U, Ustav M, Huiskonen JT, Voutilainen MH, Lindholm P, Karelson M, Saarma M. MANF regulates neuronal survival and UPR through its ER-located receptor IRE1α. Cell Rep 2023; 42:112066. [PMID: 36739529 DOI: 10.1016/j.celrep.2023.112066] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Revised: 10/20/2022] [Accepted: 01/19/2023] [Indexed: 02/05/2023] Open
Abstract
Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an endoplasmic reticulum (ER)-located protein with cytoprotective effects in neurons and pancreatic β cells in vitro and in models of neurodegeneration and diabetes in vivo. However, the exact mode of MANF action has remained elusive. Here, we show that MANF directly interacts with the ER transmembrane unfolded protein response (UPR) sensor IRE1α, and we identify the binding interface between MANF and IRE1α. The expression of wild-type MANF, but not its IRE1α binding-deficient mutant, attenuates UPR signaling by decreasing IRE1α oligomerization; phosphorylation; splicing of Xbp1, Atf6, and Txnip levels; and protecting neurons from ER stress-induced death. MANF-IRE1α interaction and not MANF-BiP interaction is crucial for MANF pro-survival activity in neurons in vitro and is required to protect dopamine neurons in an animal model of Parkinson's disease. Our data show IRE1α as an intracellular receptor for MANF and regulator of neuronal survival.
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Affiliation(s)
- Vera Kovaleva
- Institute of Biotechnology, HiLIFE, University of Helsinki, 00014 Helsinki, Finland.
| | - Li-Ying Yu
- Institute of Biotechnology, HiLIFE, University of Helsinki, 00014 Helsinki, Finland
| | - Larisa Ivanova
- Institute of Chemistry, University of Tartu, 50411 Tartu, Estonia
| | - Olesya Shpironok
- Institute of Biotechnology, HiLIFE, University of Helsinki, 00014 Helsinki, Finland
| | - Jinhan Nam
- Institute of Biotechnology, HiLIFE, University of Helsinki, 00014 Helsinki, Finland; Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, University of Helsinki, 00014 Helsinki, Finland
| | - Ave Eesmaa
- Institute of Biotechnology, HiLIFE, University of Helsinki, 00014 Helsinki, Finland
| | - Esa-Pekka Kumpula
- Institute of Biotechnology, HiLIFE, University of Helsinki, 00014 Helsinki, Finland
| | - Sven Sakson
- Institute of Biotechnology, HiLIFE, University of Helsinki, 00014 Helsinki, Finland
| | | | | | - Juha T Huiskonen
- Institute of Biotechnology, HiLIFE, University of Helsinki, 00014 Helsinki, Finland
| | - Merja H Voutilainen
- Institute of Biotechnology, HiLIFE, University of Helsinki, 00014 Helsinki, Finland; Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, University of Helsinki, 00014 Helsinki, Finland
| | - Päivi Lindholm
- Institute of Biotechnology, HiLIFE, University of Helsinki, 00014 Helsinki, Finland
| | - Mati Karelson
- Institute of Chemistry, University of Tartu, 50411 Tartu, Estonia
| | - Mart Saarma
- Institute of Biotechnology, HiLIFE, University of Helsinki, 00014 Helsinki, Finland.
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14
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Yang L, Shen WW, Shao W, Zhao Q, Pang GZ, Yang Y, Tao XF, Zhang WP, Mei Q, Shen YX. MANF ameliorates DSS-induced mouse colitis via restricting Ly6C hiCX3CR1 int macrophage transformation and suppressing CHOP-BATF2 signaling pathway. Acta Pharmacol Sin 2023; 44:1175-1190. [PMID: 36635421 DOI: 10.1038/s41401-022-01045-8] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2022] [Accepted: 12/19/2022] [Indexed: 01/14/2023]
Abstract
Mesencephalic astrocyte-derived neurotrophic factor (MANF), an endoplasmic reticulum stress-inducible secreting protein, has evolutionarily conserved immune-regulatory function that contributes to the negative regulation of inflammation in macrophages. In this study, we investigated the profiles of MANF in the macrophages of the patients with active inflammatory bowel disease (IBD) and the mice with experimental colitis, which was induced in both myeloid cell-specific MANF knockout mice and wild-type mice by 3% dextran sodium sulfate (DSS) for 7 days. We found that MANF expression was significantly increased in intestinal macrophages from both the mice with experimental colitis and patients with active IBD. DSS-induced colitis was exacerbated in myeloid cell-specific MANF knockout mice. Injection of recombinant human MANF (rhMANF, 10 mg·kg-1·d-1, i.v.) from D4 to D6 significantly ameliorated experimental colitis in DSS-treated mice. More importantly, MANF deficiency in myeloid cells resulted in a dramatic increase in the number of Ly6ChiCX3CRint proinflammatory macrophages in colon lamina propria of DSS-treated mice, and the proinflammatory cytokines and chemokines were upregulated as well. Meanwhile, we demonstrated that MANF attenuated Th17-mediated immunopathology by inhibiting BATF2-mediated innate immune response and downregulating CXCL9, CXCL10, CXCL11 and IL-12p40; MANF functioned as a negative regulator in inflammatory macrophages via inhibiting CHOP-BATF2 signaling pathway, thereby protecting against DSS-induced mouse colitis. These results suggest that MANF ameliorates colon injury by negatively regulating inflammatory macrophage transformation, which shed light on a potential therapeutic target for IBD.
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Affiliation(s)
- Lin Yang
- School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, China.,Biopharmaceutical Institute, Anhui Medical University, Hefei, 230032, China
| | - Wen-Wen Shen
- School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, China.,Biopharmaceutical Institute, Anhui Medical University, Hefei, 230032, China
| | - Wei Shao
- School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, China.,Biopharmaceutical Institute, Anhui Medical University, Hefei, 230032, China
| | - Qing Zhao
- School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, China.,Biopharmaceutical Institute, Anhui Medical University, Hefei, 230032, China
| | - Gao-Zong Pang
- School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, China.,Biopharmaceutical Institute, Anhui Medical University, Hefei, 230032, China
| | - Yi Yang
- School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, China.,Biopharmaceutical Institute, Anhui Medical University, Hefei, 230032, China.,First Affiliated Hospital of Anhui Medical University, Hefei, 230032, China
| | - Xiao-Fang Tao
- School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, China.,Biopharmaceutical Institute, Anhui Medical University, Hefei, 230032, China
| | - Wei-Ping Zhang
- First Affiliated Hospital of Anhui Medical University, Hefei, 230032, China
| | - Qiong Mei
- School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, China.,Biopharmaceutical Institute, Anhui Medical University, Hefei, 230032, China
| | - Yu-Xian Shen
- School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, China. .,Biopharmaceutical Institute, Anhui Medical University, Hefei, 230032, China.
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15
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Rehman MU, Sehar N, Dar NJ, Khan A, Arafah A, Rashid S, Rashid SM, Ganaie MA. Mitochondrial dysfunctions, oxidative stress and neuroinflammation as therapeutic targets for neurodegenerative diseases: An update on current advances and impediments. Neurosci Biobehav Rev 2023; 144:104961. [PMID: 36395982 DOI: 10.1016/j.neubiorev.2022.104961] [Citation(s) in RCA: 48] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Revised: 11/11/2022] [Accepted: 11/11/2022] [Indexed: 11/16/2022]
Abstract
Neurodegenerative diseases (NDs) such as Alzheimer disease (AD), Parkinson disease (PD), and Huntington disease (HD) represent a major socio-economic challenge in view of their high prevalence yet poor treatment outcomes affecting quality of life. The major challenge in drug development for these NDs is insufficient clarity about the mechanisms involved in pathogenesis and pathophysiology. Mitochondrial dysfunction, oxidative stress and inflammation are common pathways that are linked to neuronal abnormalities and initiation of these diseases. Thus, elucidating the shared initial molecular and cellular mechanisms is crucial for recognizing novel remedial targets, and developing therapeutics to impede or stop disease progression. In this context, use of multifunctional compounds at early stages of disease development unclogs new avenues as it acts on act on multiple targets in comparison to single target concept. In this review, we summarize overview of the major findings and advancements in recent years focusing on shared mechanisms for better understanding might become beneficial in searching more potent pharmacological interventions thereby reducing the onset or severity of various NDs.
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Affiliation(s)
- Muneeb U Rehman
- Department of Clinical Pharmacy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
| | - Nouroz Sehar
- Centre for Translational and Clinical Research, School of Chemical & Life Sciences, Jamia Hamdard, New Delhi 110062, India
| | - Nawab John Dar
- School of Medicine, University of Texas Health San Antonio, San Antonio, TX 78992 USA
| | - Andleeb Khan
- Department of Pharmacology and Toxicology, College of Pharmacy, Jazan University, Jazan 45142, Saudi Arabia
| | - Azher Arafah
- Department of Clinical Pharmacy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Summya Rashid
- Department of Pharmacology & Toxicology, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj, Saudi Arabia
| | - Shahzada Mudasir Rashid
- Division of Veterinary Biochemistry, Faculty of Veterinary Science and Animal Husbandry, SKUAST-Kashmir, Srinagar, Jammu and Kashmir, India
| | - Majid Ahmad Ganaie
- Department of Pharmacology & Toxicology, College of Dentistry and Pharmacy, Buraydah Colleges, Buraydah, Saudi Arabia
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16
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Deng H, Zhang P, Gao X, Chen W, Li J, Wang F, Gu Y, Hou X. Emerging trophic activities of mesencephalic astrocyte-derived neurotrophic factor in tissue repair and regeneration. Int Immunopharmacol 2023; 114:109598. [PMID: 36538855 DOI: 10.1016/j.intimp.2022.109598] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Revised: 12/05/2022] [Accepted: 12/12/2022] [Indexed: 12/23/2022]
Abstract
Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a soluble endoplasmic reticulum (ER) luminal protein and its expression and secretion can be induced by ER stress. Despite initially being classified as a neurotrophic factor, MANF has been demonstrated to have restorative and protective effects in many different cell types such as neurons, liver cells, retinal cells, cardiac myocytes, and pancreatic β cells. However, underlying molecular mechanisms are complex and remain incompletely understood. The aims of this review are to highlight the latest advances in the understanding of the trophic activities of MANF in tissue repair and regeneration as well as underlying molecular mechanisms. The structural motifs and immune modulation of MANF are also described. We therefore propose that MANF might be a promising therapeutic target for tissue repair.
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Affiliation(s)
- Haiyan Deng
- School of Medicine, Ningbo University, Ningbo, Zhejiang 315211, PR China
| | - Pingping Zhang
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Hefei, PR China
| | - Xianxian Gao
- School of Medicine, Ningbo University, Ningbo, Zhejiang 315211, PR China
| | - Weiyi Chen
- School of Medicine, Ningbo University, Ningbo, Zhejiang 315211, PR China
| | - Jianing Li
- School of Medicine, Ningbo University, Ningbo, Zhejiang 315211, PR China
| | - Fuyan Wang
- School of Medicine, Ningbo University, Ningbo, Zhejiang 315211, PR China; Qingdao Hospital of Traditional Chinese Medicine (Qingdao Hiser Hospital), Qingdao, 266000, PR China
| | - Yiyue Gu
- Department of Cardiology, Xuzhou No.1 Peoples Hospital, Xuzhou, PR China
| | - Xin Hou
- School of Medicine, Ningbo University, Ningbo, Zhejiang 315211, PR China; The Affiliated Hospital of Medical School, Ningbo University, Ningbo, PR China.
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17
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Liu YY, Huo D, Zeng LT, Fan GQ, Shen T, Zhang TM, Cai JP, Cui J. Mesencephalic astrocyte-derived neurotrophic factor (MANF): Structure, functions and therapeutic potential. Ageing Res Rev 2022; 82:101763. [PMID: 36272696 DOI: 10.1016/j.arr.2022.101763] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2022] [Revised: 09/18/2022] [Accepted: 10/15/2022] [Indexed: 01/31/2023]
Abstract
Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a novel evolutionarily conserved protein present in both vertebrate and invertebrate species. MANF shows distinct structural and functional properties than the traditional neurotrophic factors (NTF). MANF is composed of an N-terminal saposin-like lipid-binding domain and a C-terminal SAF-A/B, Acinus and PIAS (SAP) domain connected by a short linker. The two well-described activities of MANF include (1) role as a neurotrophic factor that plays direct neuroprotective effects in the nervous system and (2) cell protective effects in the animal models of non-neuronal diseases, including retinal damage, diabetes mellitus, liver injury, myocardial infarction, nephrotic syndrome, etc. The main objective of the current review is to provide up-to-date insights regarding the structure of MANF, mechanisms regulating its expression and secretion, physiological functions in various tissues and organs, protective effects during aging, and potential clinical applications. Together, this review highlights the importance of MANF in reversing age-related dysfunction and geroprotection.
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Affiliation(s)
- Yuan-Yuan Liu
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Science, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing, PR China
| | - Da Huo
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Science, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing, PR China
| | - Lv-Tao Zeng
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Science, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing, PR China
| | - Guo-Qing Fan
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Science, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing, PR China
| | - Tao Shen
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Science, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing, PR China
| | - Tie-Mei Zhang
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Science, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing, PR China
| | - Jian-Ping Cai
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Science, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing, PR China.
| | - Ju Cui
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Science, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing, PR China.
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18
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Eesmaa A, Yu LY, Göös H, Danilova T, Nõges K, Pakarinen E, Varjosalo M, Lindahl M, Lindholm P, Saarma M. CDNF Interacts with ER Chaperones and Requires UPR Sensors to Promote Neuronal Survival. Int J Mol Sci 2022; 23:ijms23169489. [PMID: 36012764 PMCID: PMC9408947 DOI: 10.3390/ijms23169489] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2022] [Revised: 08/16/2022] [Accepted: 08/20/2022] [Indexed: 11/16/2022] Open
Abstract
Cerebral dopamine neurotrophic factor (CDNF) is a neurotrophic factor that has beneficial effects on dopamine neurons in both in vitro and in vivo models of Parkinson's disease (PD). CDNF was recently tested in phase I-II clinical trials for the treatment of PD, but the mechanisms underlying its neuroprotective properties are still poorly understood, although studies have suggested its role in the regulation of endoplasmic reticulum (ER) homeostasis and the unfolded protein response (UPR). The aim of this study was to investigate the mechanism of action of CDNF through analyzing the involvement of UPR signaling in its anti-apoptotic function. We used tunicamycin to induce ER stress in mice in vivo and used cultured primary neurons and found that CDNF expression is regulated by ER stress in vivo and that the involvement of UPR pathways is important for the neuroprotective function of CDNF. Moreover, we used AP-MS and BiFC to perform the first interactome screening for CDNF and report novel binding partners of CDNF. These findings allowed us to hypothesize that CDNF protects neurons from ER-stress-inducing agents by modulating UPR signaling towards cell survival outcomes.
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19
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Lõhelaid H, Anttila JE, Liew HK, Tseng KY, Teppo J, Stratoulias V, Airavaara M. UPR Responsive Genes Manf and Xbp1 in Stroke. Front Cell Neurosci 2022; 16:900725. [PMID: 35783104 PMCID: PMC9240287 DOI: 10.3389/fncel.2022.900725] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Accepted: 05/02/2022] [Indexed: 11/13/2022] Open
Abstract
Stroke is a devastating medical condition with no treatment to hasten recovery. Its abrupt nature results in cataclysmic changes in the affected tissues. Resident cells fail to cope with the cellular stress resulting in massive cell death, which cannot be endogenously repaired. A potential strategy to improve stroke outcomes is to boost endogenous pro-survival pathways. The unfolded protein response (UPR), an evolutionarily conserved stress response, provides a promising opportunity to ameliorate the survival of stressed cells. Recent studies from us and others have pointed toward mesencephalic astrocyte-derived neurotrophic factor (MANF) being a UPR responsive gene with an active role in maintaining proteostasis. Its pro-survival effects have been demonstrated in several disease models such as diabetes, neurodegeneration, and stroke. MANF has an ER-signal peptide and an ER-retention signal; it is secreted by ER calcium depletion and exits cells upon cell death. Although its functions remain elusive, conducted experiments suggest that the endogenous MANF in the ER lumen and exogenously administered MANF protein have different mechanisms of action. Here, we will revisit recent and older bodies of literature aiming to delineate the expression profile of MANF. We will focus on its neuroprotective roles in regulating neurogenesis and inflammation upon post-stroke administration. At the same time, we will investigate commonalities and differences with another UPR responsive gene, X-box binding protein 1 (XBP1), which has recently been associated with MANF’s function. This will be the first systematic comparison of these two UPR responsive genes aiming at revealing previously uncovered associations between them. Overall, understanding the mode of action of these UPR responsive genes could provide novel approaches to promote cell survival.
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Affiliation(s)
- Helike Lõhelaid
- HiLIFE – Neuroscience Center, University of Helsinki, Helsinki, Finland
- *Correspondence: Helike Lõhelaid,
| | - Jenni E. Anttila
- Drug Research Program, Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland
- Individualized Drug Therapy Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Hock-Kean Liew
- Department of Medical Research, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien City, Taiwan
| | - Kuan-Yin Tseng
- Department of Neurological Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Jaakko Teppo
- Drug Research Program, Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland
| | | | - Mikko Airavaara
- HiLIFE – Neuroscience Center, University of Helsinki, Helsinki, Finland
- Drug Research Program, Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland
- Mikko Airavaara,
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20
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Wang Y, Wen W, Li H, Xu H, Xu M, Ma M, Luo J. Deficiency of mesencephalic astrocyte-derived neurotrophic factor affects neurogenesis in mouse brain. Brain Res Bull 2022; 183:49-56. [PMID: 35227768 PMCID: PMC10014018 DOI: 10.1016/j.brainresbull.2022.02.019] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Revised: 02/18/2022] [Accepted: 02/24/2022] [Indexed: 12/31/2022]
Abstract
The mechanisms underlying the regulation of neurogenesis in the adult brain remain unclear. Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a neurotrophic factor that has been implicated in various neuropathological processes and endoplasmic reticulum stress. However, the role of MANF in neurogenesis has not been investigated. Using a central nervous system (CNS)-specific Manf knock-out mouse model, we examined the role of MANF in mouse neurogenesis. We demonstrated that MANF deficiency increased BrdU labeling and Ki-67 positive cells in the subgranular zone and subventricular zone. MANF knock-out-induced upregulation of proliferative activity was accompanied by a decrease of cell cycle inhibitors (p15 and p27), an increase of G2/M marker (phospho-histone H3), as well as an increase of neural progenitor markers (Sox2 and NeuroD1) in the brain. In vitro studies using N2A neuroblastoma cells showed that the gain-of-function of MANF inhibited cell cycle progression, whereas the loss-of-function of MANF promoted cell cycle progression. Collectively, our findings indicate MANF deficiency affects cell proliferation and suggest a role of MANF in the neurogenesis of the adult brain.
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Affiliation(s)
- Yongchao Wang
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37372, USA
| | - Wen Wen
- Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
| | - Hui Li
- Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
| | - Hong Xu
- Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY 40536, USA
| | - Mei Xu
- Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY 40536, USA
| | - Murong Ma
- Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY 40536, USA
| | - Jia Luo
- Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA; Iowa City VA Health Care System, Iowa City, IA 52246, USA.
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21
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Wen W, Li H, Luo J. Potential Role of MANF, an ER Stress Responsive Neurotrophic Factor, in Protecting Against Alcohol Neurotoxicity. Mol Neurobiol 2022; 59:2992-3015. [PMID: 35254650 PMCID: PMC10928853 DOI: 10.1007/s12035-022-02786-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Accepted: 02/26/2022] [Indexed: 10/18/2022]
Abstract
Alcohol exposure during pregnancy is harmful to the fetus and causes a wide range of long-lasting physiological and neurocognitive impairments, collectively referred to as fetal alcohol spectrum disorders (FASD). The neurobehavioral deficits observed in FASD result from structural and functional damages in the brain, with neurodegeneration being the most destructive consequence. Currently, there are no therapies for FASD. It is exigent to delineate the underlying mechanisms of alcohol neurotoxicity and develop an effective strategy of treatment. ER stress, caused by the accumulation of unfolded/misfolded proteins in the ER, is the hallmark of many neurodegenerative diseases, including alcohol-induced neurodegeneration. Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a newly discovered endoplasmic reticulum (ER) stress responsive neurotrophic factor that regulates diverse neuronal functions. This review summarizes the recent findings revealing the effects of MANF on the CNS and its protective role against neurodegeneration. Particularly, we focus the role of MANF on alcohol-induced ER stress and neurodegeneration and discuss the therapeutic potential of MANF in treating alcohol neurotoxicity such as FASD.
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Affiliation(s)
- Wen Wen
- Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA, 52242, USA
| | - Hui Li
- Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA, 52242, USA
| | - Jia Luo
- Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA, 52242, USA.
- Iowa City VA Health Care System, Iowa City, IA, 52246, USA.
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22
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Tang Q, Li Y, He J. MANF: an emerging therapeutic target for metabolic diseases. Trends Endocrinol Metab 2022; 33:236-246. [PMID: 35135706 DOI: 10.1016/j.tem.2022.01.001] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Revised: 01/04/2022] [Accepted: 01/07/2022] [Indexed: 02/08/2023]
Abstract
Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an endoplasmic reticulum-resident protein and a secretory factor and has beneficial effects in multiple diseases. Recent evidence shows that its circulating levels in humans are dynamically regulated under various metabolic diseases, including diabetes, obesity, fatty liver, and cardiovascular diseases, suggesting that MANF may play a role in these pathological states. Also, its downregulation in mice impairs glucose homeostasis, promotes lipid accumulation in the liver, reduces energy expenditure, and induces inflammation. Conversely, MANF overexpression prevents or mitigates some of these metabolic disturbances. In particular, systemic MANF administration alleviates dietary obesity and related metabolic disorders in obese mice. We therefore propose that MANF might be a promising target for treating chronic metabolic diseases.
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Affiliation(s)
- Qin Tang
- Laboratory of Clinical Pharmacy and Adverse Drug Reaction, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Yanping Li
- Laboratory of Clinical Pharmacy and Adverse Drug Reaction, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Jinhan He
- Laboratory of Clinical Pharmacy and Adverse Drug Reaction, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China; Department of Pharmacy, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
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23
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Xu J, Du W, Zhao Y, Lim K, Lu L, Zhang C, Li L. Mitochondria targeting drugs for neurodegenerative diseases—design, mechanism and application. Acta Pharm Sin B 2022; 12:2778-2789. [PMID: 35755284 PMCID: PMC9214044 DOI: 10.1016/j.apsb.2022.03.001] [Citation(s) in RCA: 49] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2021] [Revised: 01/15/2022] [Accepted: 01/28/2022] [Indexed: 02/07/2023] Open
Abstract
Neurodegenerative diseases (NDDs) such as Alzheimer's disease (AD) and Parkinson's disease (PD) are a heterogeneous group of disorders characterized by progressive degeneration of neurons. NDDs threaten the lives of millions of people worldwide and regretfully remain incurable. It is well accepted that dysfunction of mitochondria underlies the pathogenesis of NDDs. Dysfunction of mitochondria results in energy depletion, oxidative stress, calcium overloading, caspases activation, which dominates the neuronal death of NDDs. Therefore, mitochondria are the preferred target for intervention of NDDs. So far various mitochondria-targeting drugs have been developed and delightfully some of them demonstrate promising outcome, though there are still some obstacles such as targeting specificity, delivery capacity hindering the drugs development. In present review, we will elaborately address 1) the strategy to design mitochondria targeting drugs, 2) the rescue mechanism of respective mitochondria targeting drugs, 3) how to evaluate the therapeutic effect. Hopefully this review will provide comprehensive knowledge for understanding how to develop more effective drugs for the treatment of NDDs.
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24
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Lindholm P, Saarma M. Cerebral dopamine neurotrophic factor protects and repairs dopamine neurons by novel mechanism. Mol Psychiatry 2022; 27:1310-1321. [PMID: 34907395 PMCID: PMC9095478 DOI: 10.1038/s41380-021-01394-6] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Revised: 11/09/2021] [Accepted: 11/15/2021] [Indexed: 12/20/2022]
Abstract
Midbrain dopamine neurons deteriorate in Parkinson's disease (PD) that is a progressive neurodegenerative movement disorder. No cure is available that would stop the dopaminergic decline or restore function of injured neurons in PD. Neurotrophic factors (NTFs), e.g., glial cell line-derived neurotrophic factor (GDNF) are small, secreted proteins that promote neuron survival during mammalian development and regulate adult neuronal plasticity, and they are studied as potential therapeutic agents for the treatment of neurodegenerative diseases. However, results from clinical trials of GDNF and related NTF neurturin (NRTN) in PD have been modest so far. In this review, we focus on cerebral dopamine neurotrophic factor (CDNF), an unconventional neurotrophic protein. CDNF delivered to the brain parenchyma protects and restores dopamine neurons in animal models of PD. In a recent Phase I-II clinical trial CDNF was found safe and well tolerated. CDNF deletion in mice led to age-dependent functional changes in the brain dopaminergic system and loss of enteric neurons resulting in slower gastrointestinal motility. These defects in Cdnf-/- mice intriguingly resemble deficiencies observed in early stage PD. Different from classical NTFs, CDNF can function both as an extracellular trophic factor and as an intracellular, endoplasmic reticulum (ER) luminal protein that protects neurons and other cell types against ER stress. Similarly to the homologous mesencephalic astrocyte-derived neurotrophic factor (MANF), CDNF is able to regulate ER stress-induced unfolded protein response (UPR) signaling and promote protein homeostasis in the ER. Since ER stress is thought to be one of the pathophysiological mechanisms contributing to the dopaminergic degeneration in PD, CDNF, and its small-molecule derivatives that are under development may provide useful tools for experimental medicine and future therapies for the treatment of PD and other neurodegenerative protein-misfolding diseases.
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Affiliation(s)
- Päivi Lindholm
- grid.7737.40000 0004 0410 2071Institute of Biotechnology, Helsinki Institute of Life Science, University of Helsinki, FI-00014 Helsinki, Finland
| | - Mart Saarma
- Institute of Biotechnology, Helsinki Institute of Life Science, University of Helsinki, FI-00014, Helsinki, Finland.
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25
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MANF: A Novel Endoplasmic Reticulum Stress Response Protein-The Role in Neurological and Metabolic Disorders. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:6467679. [PMID: 34745419 PMCID: PMC8568515 DOI: 10.1155/2021/6467679] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Accepted: 10/04/2021] [Indexed: 02/05/2023]
Abstract
The mesencephalic astrocyte-derived neurotrophic factor (MANF), also named as arginine-rich protein (ARP) or arginine-rich mutated in early-stage tumors (ARMET), is a novel evolutionary conserved protein related to unfolded protein response. Growing evidence suggests that MANF critically involves in many ER stress-related diseases with a protective effect. Here, we review the function of MANF based on its structure in neurological and metabolic disorders and summarize its potential applications in disease diagnosis and therapies.
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26
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Eremin DV, Ilchibaeva TV, Tsybko AS. Cerebral Dopamine Neurotrophic Factor (CDNF): Structure, Functions, and Therapeutic Potential. BIOCHEMISTRY (MOSCOW) 2021; 86:852-866. [PMID: 34284712 DOI: 10.1134/s0006297921070063] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
The cerebral dopamine neurotrophic factor (CDNF) together with the mesencephalic astrocyte-derived neurotrophic factor (MANF) form a unique family of neurotrophic factors (NTFs) structurally and functionally different from other proteins with neurotrophic activity. CDNF has no receptors on the cell membrane, is localized mainly in the cavity of endoplasmic reticulum (ER), and its primary function is to regulate ER stress. In addition, CDNF is able to suppress inflammation and apoptosis. Due to its functions, CDNF has demonstrated outstanding protective and restorative properties in various models of neuropathology associated with ER stress, including Parkinson's disease (PD). That is why CDNF already passed clinical trials in patients with PD. However, despite the name, CDNF functions extend far beyond the dopamine system in the brain. In particular, there are data on participation of CDNF in the maturation and maintenance of other neurotransmitter systems, regulation of the processes of neuroplasticity and non-motor behavior. In the present review, we discuss the features of CDNF structure and functions, its protective and regenerative properties.
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Affiliation(s)
- Dmitry V Eremin
- Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, 630090, Russia
| | - Tatiana V Ilchibaeva
- Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, 630090, Russia
| | - Anton S Tsybko
- Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, 630090, Russia.
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27
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Pradhan LK, Das SK. The Regulatory Role of Reticulons in Neurodegeneration: Insights Underpinning Therapeutic Potential for Neurodegenerative Diseases. Cell Mol Neurobiol 2021; 41:1157-1174. [PMID: 32504327 PMCID: PMC11448699 DOI: 10.1007/s10571-020-00893-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Accepted: 05/29/2020] [Indexed: 02/06/2023]
Abstract
In the last few decades, cytoplasmic organellar dysfunction, such as that of the endoplasmic reticulum (ER), has created a new area of research interest towards the development of serious health maladies including neurodegenerative diseases. In this context, the extensively dispersed family of ER-localized proteins, i.e. reticulons (RTNs), is gaining interest because of its regulative control over neural regeneration. As most neurodegenerative diseases are pathologically manifested with the accretion of misfolded proteins with subsequent induction of ER stress, the regulatory role of RTNs in neural dysfunction cannot be ignored. With the limited information available in the literature, delineation of the functional connection between rising consequences of neurodegenerative diseases and RTNs need to be elucidated. In this review, we provide a broad overview on the recently revealed regulatory roles of reticulons in the pathophysiology of several health maladies, with special emphasis on neurodegeneration. Additionally, we have also recapitulated the decisive role of RTN4 in neurite regeneration and highlighted how neurodegeneration and proteinopathies are mechanistically linked with each other through specific RTN paralogues. With the recent findings advocating zebrafish Rtn4b (a mammalian Nogo-A homologue) downregulation following central nervous system (CNS) lesion, RTNs provides new insight into the CNS regeneration. However, there are controversies with respect to the role of Rtn4b in zebrafish CNS regeneration. Given these controversies, the connection between the unique regenerative capabilities of zebrafish CNS by distinct compensatory mechanisms and Rtn4b signalling pathway could shed light on the development of new therapeutic strategies against serious neurodegenerative diseases.
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Affiliation(s)
- Lilesh Kumar Pradhan
- Neurobiology Laboratory, Centre for Biotechnology, Siksha 'O' Anusandhan (Deemed To Be University), Kalinga Nagar, Bhubaneswar, 751003, India
| | - Saroj Kumar Das
- Neurobiology Laboratory, Centre for Biotechnology, School of Pharmaceutical Sciences, Siksha 'O' Anusandhan (Deemed To Be University), Kalinga Nagar, Bhubaneswar, 751003, India.
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28
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Liu XC, Qi XH, Fang H, Zhou KQ, Wang QS, Chen GH. Increased MANF Expression in the Inferior Temporal Gyrus in Patients With Alzheimer Disease. Front Aging Neurosci 2021; 13:639318. [PMID: 33994992 PMCID: PMC8117094 DOI: 10.3389/fnagi.2021.639318] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Accepted: 04/08/2021] [Indexed: 11/21/2022] Open
Abstract
Alzheimer disease (AD) is an aging-related disorder linked to endoplasmic reticulum (ER) stress. The main pathologic feature of AD is the presence of extracellular senile plaques and intraneuronal neurofibrillary tangles (NFTs) in the brain. In neurodegenerative diseases, the unfolded protein response (UPR) induced by ER stress ensures cell survival. Mesencephalic astrocyte-derived neurotrophic factor (MANF) protects against ER stress and has been implicated in the pathogenesis of AD. MANF is expressed in neurons of the brain and spinal cord. However, there have been no investigations on MANF expression in the brain of AD patients. This was addressed in the present study by immunohistochemistry, western blotting, and quantitative analyses of postmortem brain specimens. We examined the localization and expression levels of MANF in the inferior temporal gyrus of the cortex (ITGC) in AD patients (n = 5), preclinical (pre-)AD patients (n = 5), and age-matched non-dementia controls (n = 5) by double immunofluorescence labeling with antibodies against the neuron-specific nuclear protein neuronal nuclei (NeuN), ER chaperone protein 78-kDa glucose-regulated protein (GRP78), and MANF. The results showed that MANF was mainly expressed in neurons of the ITGC in all 3 groups; However, the number of MANF-positive neurons was significantly higher in pre-AD (Braak stage III/IV) and AD (Braak stage V/VI) patients than that in the control group. Thus, MANF is overexpressed in AD and pre-AD, suggesting that it can serve as a diagnostic marker for early stage disease.
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Affiliation(s)
- Xue-Chun Liu
- Department of Neurology (Sleep Disorders), The Affiliated Chaohu Hospital of Anhui Medical University, Hefei, China.,Department of Neurology, Chinese PLA Clinical College, Anhui Medical University, Hefei, China
| | - Xiu-Hong Qi
- Hefei National Laboratory for Physical Sciences at the Microscale, School of Life Sciences, Chinese Academy of Sciences Key Laboratory of Brain Function and Diseases, University of Science and Technology of China, Hefei, China
| | - Hui Fang
- Hefei National Laboratory for Physical Sciences at the Microscale, School of Life Sciences, Chinese Academy of Sciences Key Laboratory of Brain Function and Diseases, University of Science and Technology of China, Hefei, China
| | - Ke-Qing Zhou
- Hefei National Laboratory for Physical Sciences at the Microscale, School of Life Sciences, Chinese Academy of Sciences Key Laboratory of Brain Function and Diseases, University of Science and Technology of China, Hefei, China
| | - Qing-Song Wang
- Department of Neurology, Chinese PLA Clinical College, Anhui Medical University, Hefei, China
| | - Gui-Hai Chen
- Department of Neurology (Sleep Disorders), The Affiliated Chaohu Hospital of Anhui Medical University, Hefei, China
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29
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Yang Y, Wang P, Zhang C, Huang F, Pang G, Wei C, Lv C, Chhetri G, Jiang T, Liu J, Shen Y, Shen Y. Hepatocyte-derived MANF alleviates hepatic ischaemia-reperfusion injury via regulating endoplasmic reticulum stress-induced apoptosis in mice. Liver Int 2021; 41:623-639. [PMID: 33064897 DOI: 10.1111/liv.14697] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2020] [Revised: 09/30/2020] [Accepted: 10/05/2020] [Indexed: 12/14/2022]
Abstract
BACKGROUND Endoplasmic reticulum (ER) perturbations are novel subcellular effectors involved in the ischaemia-reperfusion injury. As an ER stress-inducible protein, mesencephalic astrocyte-derived neurotrophic factor (MANF) has been proven to be increased during ischaemic brain injury. However, the role of MANF in liver ischaemia reperfusion (I/R) injury has not yet been studied. METHODS To investigate the role of MANF in the process of liver ischaemia-reperfusion, Hepatocyte-specific MANF knockout (MANFhep-/- ) mice and their wild-type (WT) littermates were used in our research. Mice partial (70%) warm hepatic I/R model was established by vascular occlusion. We detected the serum levels of MANF in both liver transplant patients and WT mice before and after liver I/R injury. Recombinant human MANF (rhMANF) was injected into the tail vein before 1 hour occlusion. AST, ALT and Suzuki score were used to evaluate the extent of I/R injury. OGD/R test was performed on primary hepatocytes to simulate IRI in vitro. RNA sequence and RT-PCR were used to detect the cellular signal pathway activation while MANF knockout. RESULTS We found that MANF expression and secretion are dramatically up-regulated during hepatic I/R. Hepatocyte-specific MANF knockout aggravates the I/R injury through the over-activated ER stress. The systemic administration of rhMANF before ischaemia has the potential to ameliorate I/R-triggered UPR and liver injury. Further study showed that MANF deficiency activated ATF4/CHOP and JNK/c-JUN/CHOP pathways, and rhMANF inhibited the activation of the two proapoptotic pathways caused by MANF deletion. CONCLUSION Collectively, our study unravels a previously unknown relationship among MANF, UPR and hepatic I/R injury.
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Affiliation(s)
- Yi Yang
- School of Basic Medical Sciences, Anhui Medical University, Hefei, China.,Biopharmaceutical Institute, Anhui Medical University, Hefei, China
| | - Peng Wang
- School of Basic Medical Sciences, Anhui Medical University, Hefei, China.,Biopharmaceutical Institute, Anhui Medical University, Hefei, China
| | - Chaoyi Zhang
- School of Basic Medical Sciences, Anhui Medical University, Hefei, China.,Biopharmaceutical Institute, Anhui Medical University, Hefei, China
| | - Fan Huang
- First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Gaozong Pang
- School of Basic Medical Sciences, Anhui Medical University, Hefei, China.,Biopharmaceutical Institute, Anhui Medical University, Hefei, China
| | - Chuansheng Wei
- School of Basic Medical Sciences, Anhui Medical University, Hefei, China.,Biopharmaceutical Institute, Anhui Medical University, Hefei, China
| | - Changming Lv
- School of Basic Medical Sciences, Anhui Medical University, Hefei, China.,Biopharmaceutical Institute, Anhui Medical University, Hefei, China
| | - Goma Chhetri
- School of Basic Medical Sciences, Anhui Medical University, Hefei, China.,Biopharmaceutical Institute, Anhui Medical University, Hefei, China
| | - Tongcui Jiang
- School of Basic Medical Sciences, Anhui Medical University, Hefei, China.,Biopharmaceutical Institute, Anhui Medical University, Hefei, China
| | - Jun Liu
- School of Basic Medical Sciences, Anhui Medical University, Hefei, China.,Biopharmaceutical Institute, Anhui Medical University, Hefei, China
| | - Yujun Shen
- School of Basic Medical Sciences, Anhui Medical University, Hefei, China.,Biopharmaceutical Institute, Anhui Medical University, Hefei, China
| | - Yuxian Shen
- School of Basic Medical Sciences, Anhui Medical University, Hefei, China.,Biopharmaceutical Institute, Anhui Medical University, Hefei, China
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30
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Eesmaa A, Yu LY, Göös H, Nõges K, Kovaleva V, Hellman M, Zimmermann R, Jung M, Permi P, Varjosalo M, Lindholm P, Saarma M. The cytoprotective protein MANF promotes neuronal survival independently from its role as a GRP78 cofactor. J Biol Chem 2021; 296:100295. [PMID: 33460650 PMCID: PMC7949057 DOI: 10.1016/j.jbc.2021.100295] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2020] [Revised: 01/07/2021] [Accepted: 01/12/2021] [Indexed: 12/14/2022] Open
Abstract
Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an endoplasmic reticulum (ER)-stress-regulated protein exhibiting cytoprotective properties through a poorly understood mechanism in various in vitro and in vivo models of neuronal and non-neuronal damage. Although initially characterized as a secreted neurotrophic factor for midbrain dopamine neurons, MANF has recently gained more interest for its intracellular role in regulating the ER homeostasis, including serving as a cofactor of the chaperone glucose-regulated protein 78 (GRP78). We aimed for a better understanding of the neuroprotective mechanisms of MANF. Here we show for the first time that MANF promotes the survival of ER-stressed neurons in vitro as a general unfolded protein response (UPR) regulator, affecting several UPR pathways simultaneously. Interestingly, MANF does not affect naïve neurons. We hypothesize that MANF regulates UPR signaling toward a mode more compatible with neuronal survival. Screening of MANF interacting proteins from two mammalian cell lines revealed a conserved interactome of 15 proteins including several ER chaperones such as GRP78, GRP170, protein disulfide isomerase family A member 1, and protein disulfide isomerase family A member 6. Further characterization confirmed previously published finding that MANF is a cofactor of GRP78 interacting with its nucleotide binding domain. Using microscale thermophoresis and nuclear magnetic resonance spectroscopy, we discovered that MANF is an ATP binding protein and that ATP blocks the MANF-GRP78 interaction. Interestingly, functional analysis of the antiapoptotic properties of MANF mutants in cultured neurons revealed divergent roles of MANF as a GRP78 cofactor and as an antiapoptotic regulator of UPR. We conclude that the co-factor type interaction with GRP78 is dispensable for the survival-promoting activity of MANF in neurons.
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Affiliation(s)
- Ave Eesmaa
- Institute of Biotechnology, HiLIFE, University of Helsinki, Helsinki, Finland
| | - Li-Ying Yu
- Institute of Biotechnology, HiLIFE, University of Helsinki, Helsinki, Finland
| | - Helka Göös
- Institute of Biotechnology, HiLIFE, University of Helsinki, Helsinki, Finland
| | - Kristofer Nõges
- Institute of Biotechnology, HiLIFE, University of Helsinki, Helsinki, Finland
| | - Vera Kovaleva
- Institute of Biotechnology, HiLIFE, University of Helsinki, Helsinki, Finland
| | - Maarit Hellman
- Department of Chemistry, Nanoscience Center, University of Jyväskylä, Jyväskylä, Finland
| | - Richard Zimmermann
- Medical Biochemistry and Molecular Biology, Saarland University, Homburg, Germany
| | - Martin Jung
- Medical Biochemistry and Molecular Biology, Saarland University, Homburg, Germany
| | - Perttu Permi
- Department of Chemistry, Nanoscience Center, University of Jyväskylä, Jyväskylä, Finland; Department of Biological and Environmental Science, Nanoscience Center, University of Jyväskylä, Jyväskylä, Finland
| | - Markku Varjosalo
- Institute of Biotechnology, HiLIFE, University of Helsinki, Helsinki, Finland
| | - Päivi Lindholm
- Institute of Biotechnology, HiLIFE, University of Helsinki, Helsinki, Finland.
| | - Mart Saarma
- Institute of Biotechnology, HiLIFE, University of Helsinki, Helsinki, Finland.
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Kovaleva V, Saarma M. Endoplasmic Reticulum Stress Regulators: New Drug Targets for Parkinson's Disease. JOURNAL OF PARKINSON'S DISEASE 2021; 11:S219-S228. [PMID: 34180421 PMCID: PMC8543257 DOI: 10.3233/jpd-212673] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Accepted: 05/19/2021] [Indexed: 02/06/2023]
Abstract
Parkinson's disease (PD) pathology involves progressive degeneration and death of vulnerable dopamine neurons in the substantia nigra. Extensive axonal arborization and distinct functions make this type of neurons particularly sensitive to homeostatic perturbations, such as protein misfolding and Ca2+ dysregulation. Endoplasmic reticulum (ER) is a cell compartment orchestrating protein synthesis and folding, as well as synthesis of lipids and maintenance of Ca2+ homeostasis in eukaryotic cells. When misfolded proteins start to accumulate in ER lumen the unfolded protein response (UPR) is activated. UPR is an adaptive signaling machinery aimed at relieving of protein folding load in the ER. When UPR is chronic, it can either boost neurodegeneration and apoptosis or cause neuronal dysfunctions. We have recently discovered that mesencephalic astrocyte-derived neurotrophic factor (MANF) exerts its prosurvival action in dopamine neurons and in an animal model of PD through the direct binding to UPR sensor inositol-requiring protein 1 alpha (IRE1α) and attenuation of UPR. In line with this, UPR targeting resulted in neuroprotection and neurorestoration in various preclinical animal models of PD. Therefore, growth factors (GFs), possessing both neurorestorative activity and restoration of protein folding capacity are attractive as drug candidates for PD treatment especially their blood-brain barrier penetrating analogs and small molecule mimetics. In this review, we discuss ER stress as a therapeutic target to treat PD; we summarize the existing preclinical data on the regulation of ER stress for PD treatment. In addition, we point out the crucial aspects for successful clinical translation of UPR-regulating GFs and new prospective in GFs-based treatments of PD, focusing on ER stress regulation.
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Affiliation(s)
- Vera Kovaleva
- Institute of Biotechnology, HiLIFE, University of Helsinki, Finland
| | - Mart Saarma
- Institute of Biotechnology, HiLIFE, University of Helsinki, Finland
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Wang Y, Wen W, Li H, Clementino M, Xu H, Xu M, Ma M, Frank J, Luo J. MANF is neuroprotective against ethanol-induced neurodegeneration through ameliorating ER stress. Neurobiol Dis 2021; 148:105216. [PMID: 33296727 PMCID: PMC7856049 DOI: 10.1016/j.nbd.2020.105216] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Revised: 11/18/2020] [Accepted: 12/03/2020] [Indexed: 12/23/2022] Open
Abstract
Fetal alcohol spectrum disorders (FASD) are a spectrum of developmental disorders caused by prenatal alcohol exposure. Neuronal loss or neurodegeneration in the central nervous system (CNS) is one of the most devastating features in FASD. It is imperative to delineate the underlying mechanisms to facilitate the treatment of FASD. Endoplasmic reticulum (ER) stress is a hallmark and an underlying mechanism of many neurodegenerative diseases, including ethanol-induced neurodegeneration. Mesencephalic astrocyte-derived neurotrophic factor (MANF) responds to ER stress and has been identified as a protein upregulated in response to ethanol exposure during the brain development. To investigate the role of MANF in ethanol-induced neurodegeneration and its association with ER stress regulation, we established a CNS-specific Manf knockout mouse model and examined the effects of MANF deficiency on ethanol-induced neuronal apoptosis and ER stress using a third-trimester equivalent mouse model. We found MANF deficiency exacerbated ethanol-induced neuronal apoptosis and ER stress and that blocking ER stress abrogated the harmful effects of MANF deficiency on ethanol-induced neuronal apoptosis. Moreover, using an animal model of ER-stress-induced neurodegeneration, we demonstrated that MANF deficiency potentiated tunicamycin (TM)-induced ER stress and neurodegeneration. A whole transcriptome RNA sequencing also supported the functionality of MANF in ER stress modulation and revealed targets that may mediate the ER stress-buffering capacity of MANF. Collectively, these results suggest that MANF is a neurotrophic factor that can protect neurons against ethanol-induced neurodegeneration by ameliorating ER stress.
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Affiliation(s)
- Yongchao Wang
- Department of Cell and Development Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, United States of America
| | - Wen Wen
- Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, United States of America
| | - Hui Li
- Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, United States of America
| | - Marco Clementino
- Department of Toxicology and Cancer Biology, University of Kentucky College of Medicine, Lexington, KY 40536, United States of America
| | - Hong Xu
- Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY 40536, United States of America
| | - Mei Xu
- Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY 40536, United States of America
| | - Murong Ma
- Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY 40536, United States of America
| | - Jacqueline Frank
- Department of Neurology, University of Kentucky College of Medicine, Lexington, KY 40536, United States of America
| | - Jia Luo
- Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, United States of America; Iowa City VA Health Care System, Iowa City, IA 52246, United States of America.
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Sidorova YA, Saarma M. Can Growth Factors Cure Parkinson's Disease? Trends Pharmacol Sci 2020; 41:909-922. [PMID: 33198924 DOI: 10.1016/j.tips.2020.09.010] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2020] [Revised: 09/25/2020] [Accepted: 09/30/2020] [Indexed: 01/03/2023]
Abstract
Growth factors (GFs) hold considerable promise for disease modification in neurodegenerative disorders because they can protect and restore degenerating neurons and also enhance their functional activity. However, extensive efforts applied to utilize their therapeutic potential in humans have achieved limited success so far. Multiple clinical trials with GFs were performed in Parkinson's disease (PD) patients, in whom diagnostic symptoms of the disease are caused by advanced degeneration of nigrostriatal dopamine neurons (DNs), but the results of these trials are controversial. This review discusses recent developments in the field of therapeutic use of GFs, problems and obstacles related to this use, suggests the ways to overcome these issues, and alternative approaches that can be used to utilize the potential ofGFsin PD management.
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Affiliation(s)
- Yulia A Sidorova
- Institute of Biotechnology, HiLIFE, University of Helsinki, Helsinki, Finland
| | - Mart Saarma
- Institute of Biotechnology, HiLIFE, University of Helsinki, Helsinki, Finland.
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Wen W, Wang Y, Li H, Xu H, Xu M, Frank JA, Ma M, Luo J. Mesencephalic Astrocyte-Derived Neurotrophic Factor (MANF) Regulates Neurite Outgrowth Through the Activation of Akt/mTOR and Erk/mTOR Signaling Pathways. Front Mol Neurosci 2020; 13:560020. [PMID: 33071755 PMCID: PMC7541815 DOI: 10.3389/fnmol.2020.560020] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Accepted: 09/04/2020] [Indexed: 12/13/2022] Open
Abstract
Neurite outgrowth is essential for brain development and the recovery of brain injury and neurodegenerative diseases. In this study, we examined the role of the neurotrophic factor MANF in regulating neurite outgrowth. We generated MANF knockout (KO) neuro2a (N2a) cell lines using clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 and demonstrated that MANF KO N2a cells failed to grow neurites in response to RA stimulation. Using MANF siRNA, this finding was confirmed in human SH-SY5Y neuronal cell line. Nevertheless, MANF overexpression by adenovirus transduction or addition of MANF into culture media facilitated the growth of longer neurites in RA-treated N2a cells. MANF deficiency resulted in inhibition of Akt, Erk, mTOR, and P70S6, and impaired protein synthesis. MANF overexpression on the other hand facilitated the growth of longer neurites by activating Akt, Erk, mTOR, and P70S6. Pharmacological blockade of Akt, Erk or mTOR eliminated the promoting effect of MANF on neurite outgrowth. These findings suggest that MANF positively regulated neurite outgrowth by activating Akt/mTOR and Erk/mTOR signaling pathways.
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Affiliation(s)
- Wen Wen
- Department of Pathology, University of Iowa, Iowa City, IA, United States
| | - Yongchao Wang
- Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY, United States
| | - Hui Li
- Department of Pathology, University of Iowa, Iowa City, IA, United States
| | - Hong Xu
- Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY, United States
| | - Mei Xu
- Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY, United States
| | - Jacqueline A Frank
- Department of Neurology, University of Kentucky College of Medicine, Lexington, KY, United States
| | - Murong Ma
- Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY, United States
| | - Jia Luo
- Department of Pathology, University of Iowa, Iowa City, IA, United States
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Yang F, Li WB, Qu YW, Gao JX, Tang YS, Wang DJ, Pan YJ. Bone marrow mesenchymal stem cells induce M2 microglia polarization through PDGF-AA/MANF signaling. World J Stem Cells 2020; 12:633-658. [PMID: 32843919 PMCID: PMC7415242 DOI: 10.4252/wjsc.v12.i7.633] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2020] [Revised: 04/04/2020] [Accepted: 05/17/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Bone marrow mesenchymal stem cells (BMSCs) are capable of shifting the microglia/macrophages phenotype from M1 to M2, contributing to BMSCs-induced brain repair. However, the regulatory mechanism of BMSCs on microglia/macrophages after ischemic stroke is unclear. Recent evidence suggests that mesencephalic astrocyte–derived neurotrophic factor (MANF) and platelet-derived growth factor-AA (PDGF-AA)/MANF signaling regulate M1/M2 macrophage polarization.
AIM To investigate whether and how MANF or PDGF-AA/MANF signaling influences BMSCs-mediated M2 polarization.
METHODS We identified the secretion of MANF by BMSCs and developed transgenic BMSCs using a targeting small interfering RNA for knockdown of MANF expression. Using a rat middle cerebral artery occlusion (MCAO) model transplanted by BMSCs and BMSCs–microglia Transwell coculture system, the effect of BMSCs-induced downregulation of MANF expression on the phenotype of microglia/macrophages was tested by Western blot, quantitative reverse transcription-polymerase chain reaction, and immunofluorescence. Additionally, microglia were transfected with mimics of miR-30a*, which influenced expression of X-box binding protein (XBP) 1, a key transcription factor that synergized with activating transcription factor 6 (ATF6) to govern MANF expression. We examined the levels of miR-30a*, ATF6, XBP1, and MANF after PDGF-AA treatment in the activated microglia.
RESULTS Inhibition of MANF attenuated BMSCs-induced functional recovery and decreased M2 marker production, but increased M1 marker expression in vivo or in vitro. Furthermore, PDGF-AA treatment decreased miR-30a* expression, had no influence on the levels of ATF6, but enhanced expression of both XBP1 and MANF.
CONCLUSION BMSCs-mediated MANF paracrine signaling, in particular the PDGF-AA/miR-30a*/XBP1/MANF pathway, synergistically mediates BMSCs-induced M2 polarization.
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Affiliation(s)
- Fan Yang
- Department of Neurology, The First Clinical College of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
| | - Wen-Bin Li
- Department of Neurology, The First Clinical College of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
| | - Ye-Wei Qu
- Department of Neurology, The First Clinical College of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
| | - Jin-Xing Gao
- Department of Neurology, The First Clinical College of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
| | - Yu-Shi Tang
- Department of Neurology, The First Clinical College of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
| | - Dong-Jie Wang
- Department of Respiratory Medicine, The First Clinical College of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
| | - Yu-Jun Pan
- Department of Neurology, The First Clinical College of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
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Role of Mesencephalic Astrocyte-Derived Neurotrophic Factor in Alcohol-Induced Liver Injury. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2020; 2020:9034864. [PMID: 32724497 PMCID: PMC7364207 DOI: 10.1155/2020/9034864] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/19/2020] [Accepted: 05/29/2020] [Indexed: 12/20/2022]
Abstract
Consumption of alcohol in immoderate quantity induces endoplasmic reticulum (ER) stress response (alcohol-induced ER stress). Mesencephalic astrocyte-derived neurotrophic factor (MANF), an ER stress-inducible protein, works as an evolutionarily conserved regulator of systemic and liver metabolic homeostasis. In this study, the effects of MANF on alcohol-induced liver injury were explored by using hepatocyte-specific MANF-knockout mice (MANF ΔHep) in a chronic-plus-binge alcohol feeding model. We found that alcohol feeding upregulated MANF expression and MANF ΔHep mice exhibited more severe liver injury with extra activated ER stress after alcohol feeding. In addition, we found that MANF deficiency activated iNOS and p65 and increased the production of NO and anti-inflammatory cytokines, which was further enhanced after alcohol treatment. Meanwhile, MANF deletion upregulated the levels of CYP2E1, 4-HNE, and MDA and downregulated the levels of GSH and SOD. These results indicate that MANF has potential protection on alcohol-induced liver injury, and the underlying mechanisms may be associated with meliorating the overactivated ER stress triggered by inflammation and oxidative stress via inhibiting and reducing NO/NF-κB and CYP2E1/ROS, respectively. Therefore, MANF might be a negative regulator in alcohol-induced ER stress and participate in the crosstalk between the NF-κB pathway and oxidative stress in the liver. Conclusions. This study identifies a specific role of MANF in alcohol-induced liver injury, which may provide a new approach for the treatment of ALI.
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Teppo J, Vaikkinen A, Stratoulias V, Mätlik K, Anttila JE, Smolander OP, Pöhö P, Harvey BK, Kostiainen R, Airavaara M. Molecular profile of the rat peri-infarct region four days after stroke: Study with MANF. Exp Neurol 2020; 329:113288. [PMID: 32229226 PMCID: PMC11924106 DOI: 10.1016/j.expneurol.2020.113288] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Revised: 02/27/2020] [Accepted: 03/25/2020] [Indexed: 12/12/2022]
Abstract
The peri-infarct region after ischemic stroke is the anatomical location for many of the endogenous recovery processes; however, -the molecular events in the peri-infarct region remain poorly characterized. In this study, we examine the molecular profile of the peri-infarct region on post-stroke day four, a time when reparative processes are ongoing. We used a multiomics approach, involving RNA sequencing, and mass spectrometry-based proteomics and metabolomics to characterize molecular changes in the peri-infarct region. We also took advantage of our previously developed method to express transgenes in the peri-infarct region where self-complementary adeno-associated virus (AAV) vectors were injected into the brain parenchyma on post-stroke day 2. We have previously used this method to show that mesencephalic astrocyte-derived neurotrophic factor (MANF) enhances functional recovery from stroke and recruits phagocytic cells to the peri-infarct region. Here, we first analyzed the effects of stroke to the peri-infarct region on post-stroke day 4 in comparison to sham-operated animals, finding that strokeinduced changes in 3345 transcripts, 341 proteins, and 88 metabolites. We found that after stroke, genes related to inflammation, proliferation, apoptosis, and regeneration were upregulated, whereas genes encoding neuroactive ligand receptors and calcium-binding proteins were downregulated. In proteomics, we detected upregulation of proteins related to protein synthesis and downregulation of neuronal proteins. Metabolomic studies indicated that in after stroke tissue there is an increase in saccharides, sugar phosphates, ceramides and free fatty acids and a decrease of adenine, hypoxantine, adenosine and guanosine. We then compared the effects of post-stroke delivery of AAV1-MANF to AAV1-eGFP (enhanced green fluorescent protein). MANF administration increased the expression of 77 genes, most of which were related to immune response. In proteomics, MANF administration reduced S100A8 and S100A9 protein levels. In metabolomics, no significant differences between MANF and eGFP treatment were detected, but relative to sham surgery group, most of the changes in lipids were significant in the AAV-eGFP group only. This work describes the molecular profile of the peri-infarct region during recovery from ischemic stroke, and establishes a resource for further stroke studies. These results provide further support for parenchymal MANF as a modulator of phagocytic function.
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Affiliation(s)
- Jaakko Teppo
- Drug Research Program and Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, Finland; Institute of Biotechnology, HiLIFE, University of Helsinki, Finland
| | - Anu Vaikkinen
- Drug Research Program and Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, Finland
| | - Vassilis Stratoulias
- Institute of Biotechnology, HiLIFE, University of Helsinki, Finland; Neuroscience Center, HiLIFE, University of Helsinki, Finland
| | - Kert Mätlik
- Institute of Biotechnology, HiLIFE, University of Helsinki, Finland
| | - Jenni E Anttila
- Institute of Biotechnology, HiLIFE, University of Helsinki, Finland
| | - Olli-Pekka Smolander
- Department of Chemistry and Biotechnology, Tallinn University of Technology, Estonia
| | - Päivi Pöhö
- Drug Research Program and Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, Finland
| | | | - Risto Kostiainen
- Drug Research Program and Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, Finland.
| | - Mikko Airavaara
- Institute of Biotechnology, HiLIFE, University of Helsinki, Finland; Neuroscience Center, HiLIFE, University of Helsinki, Finland.
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MANF Ablation Causes Prolonged Activation of the UPR without Neurodegeneration in the Mouse Midbrain Dopamine System. eNeuro 2020; 7:ENEURO.0477-19.2019. [PMID: 32005751 PMCID: PMC7053174 DOI: 10.1523/eneuro.0477-19.2019] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2019] [Revised: 12/20/2019] [Accepted: 12/20/2019] [Indexed: 01/08/2023] Open
Abstract
Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an endoplasmic reticulum (ER) localized protein that regulates ER homeostasis and unfolded protein response (UPR). The biology of endogenous MANF in the mammalian brain is unknown and therefore we studied the brain phenotype of MANF-deficient female and male mice at different ages focusing on the midbrain dopamine system and cortical neurons. We show that a lack of MANF from the brain led to the chronic activation of UPR by upregulation of the endoribonuclease activity of the inositol-requiring enzyme 1α (IRE1α) pathway. Furthermore, in the aged MANF-deficient mouse brain in addition the protein kinase-like ER kinase (PERK) and activating transcription factor 6 (ATF6) branches of the UPR pathways were activated. Neuronal loss in neurodegenerative diseases has been associated with chronic ER stress. In our mouse model, increased UPR activation did not lead to neuronal cell loss in the substantia nigra (SN), decrease of striatal dopamine or behavioral changes of MANF-deficient mice. However, cortical neurons lacking MANF were more vulnerable to chemical induction of additional ER stress in vitro. We conclude that embryonic neuronal deletion of MANF does not cause the loss of midbrain dopamine neurons in mice. However, endogenous MANF is needed for maintenance of neuronal ER homeostasis both in vivo and in vitro.
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Deficiency of the ER-stress-regulator MANF triggers progressive outer hair cell death and hearing loss. Cell Death Dis 2020; 11:100. [PMID: 32029702 PMCID: PMC7005028 DOI: 10.1038/s41419-020-2286-6] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2019] [Revised: 01/16/2020] [Accepted: 01/17/2020] [Indexed: 11/28/2022]
Abstract
The non-conventional neurotrophic factor mesencephalic astrocyte-derived neurotrophic factor (MANF) is an endoplasmic reticulum (ER)-resident protein that promotes ER homeostasis. MANF has a cytoprotective function, shown in the central nervous system neurons and pancreatic beta cells. Here, we report that MANF is expressed in the hair cells and neurons and in selected non-sensory cells of the cochlea and that Manf inactivation triggers upregulation of the ER chaperones in these cells. However, Manf inactivation resulted in the death of only outer hair cells (OHCs), the cells responsible for sound amplification in the cochlea. All OHCs were formed in Manf-inactivated mice, but progressive OHC death started soon after the onset of hearing function. The robust OHC loss was accompanied by strongly elevated hearing thresholds. Conditional Manf inactivation demonstrated that MANF has a local function in the cochlea. Immunostainings revealed the upregulation of CHOP, the pro-apoptotic component of the unfolded protein response (UPR), in Manf-inactivated OHCs, linking the UPR to the loss of these cells. The phenotype of Manf-inactivated OHCs was distinctly dependent on the mouse strain, such that the strains characterized by early-onset age-related hearing loss (C57BL/6J and CD-1) were affected. These results suggest that Manf deficiency becomes detrimental when accompanied by gene mutations that predispose to hearing loss, by intensifying ER dyshomeostasis. Together, MANF is the first growth factor shown to antagonize ER stress-mediated OHC death. MANF might serve as a therapeutic candidate for protection against hearing loss induced by the ER-machinery-targeting stressors.
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40
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Albert K, Airavaara M. Neuroprotective and reparative effects of endoplasmic reticulum luminal proteins - mesencephalic astrocyte-derived neurotrophic factor and cerebral dopamine neurotrophic factor. Croat Med J 2019. [PMID: 31044581 PMCID: PMC6509620 DOI: 10.3325/cmj.2019.60.99] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Cerebral dopamine neurotrophic factor (CDNF) and mesencephalic astrocyte-derived neurotrophic factor (MANF) are proteins that have received increasing attention in the last decades. Although they are called neurotrophic factors they are drastically different from neurotrophic factors in their expression and physiological actions. They are located in the lumen of the endoplasmic reticulum (ER) and their basal secretion from neurons is very low. However their secretion is stimulated upon ER calcium depletion by chemical probes such as thapsigargin, a sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) pump inhibitor. Exogenous MANF and CDNF possess therapeutic properties in several neurological disease models, including Parkinson’s disease and stroke. Endogenous MANF expression has been shown to be neuroprotective, as well as administration of either CDNF or MANF into the extracellular space. In this review, we focus on their therapeutic effects, regulation of expression and secretion, comparison of their mechanisms of action, and their application to the brain parenchyma as recombinant proteins.
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Affiliation(s)
| | - Mikko Airavaara
- Mikko Airavaara, Neuroscience Center, HiLIFE, P.O. Box 63, 00014 University of Helsinki, Helsinki, Finland,
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41
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Hartman JH, Richie CT, Gordon KL, Mello DF, Castillo P, Zhu A, Wang Y, Hoffer BJ, Sherwood DR, Meyer JN, Harvey BK. MANF deletion abrogates early larval Caenorhabditis elegans stress response to tunicamycin and Pseudomonas aeruginosa. Eur J Cell Biol 2019; 98:151043. [PMID: 31138438 DOI: 10.1016/j.ejcb.2019.05.002] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2018] [Revised: 04/16/2019] [Accepted: 05/20/2019] [Indexed: 02/06/2023] Open
Abstract
Mesencephalic astrocyte-derived neurotrophic factor (MANF) is the only human neurotrophic factor with an evolutionarily-conserved C. elegans homolog, Y54G2A.23 or manf-1. MANF is a small, soluble, endoplasmic-reticulum (ER)-resident protein that is secreted upon ER stress and promotes survival of target cells such as neurons. However, the role of MANF in ER stress and its mechanism of cellular protection are not clear and the function of MANF in C. elegans is only beginning to emerge. In this study, we show that depletion of C. elegans manf-1 causes a slight decrease in lifespan and brood size; furthermore, combined depletion of manf-1 and the IRE-1/XBP-1 ER stress/UPR pathway resulted in sterile animals that did not produce viable progeny. We demonstrate upregulation of markers of ER stress in L1 larval nematodes, as measured by hsp-3 and hsp-4 transcription, upon depletion of manf-1 by RNAi or mutation; however, there was no difference in tunicamycin-induced expression of hsp-3 and hsp-4 between wild-type and MANF-deficient worms. Surprisingly, larval growth arrest observed in wild-type nematodes reared on tunicamycin is completely prevented in the manf-1 (tm3603) mutant. Transcriptional microarray analysis revealed that manf-1 mutant L1 larvae exhibit a novel modulation of innate immunity genes in response to tunicamycin. The hypothesis that manf-1 negatively regulates the innate immunity pathway is supported by our finding that the development of manf-1 mutant larvae compared to wild-type larvae is not inhibited by growth on P. aeruginosa. Together, our data represent the first characterization of C. elegans MANF as a key modulator of organismal ER stress and immunity.
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Affiliation(s)
- Jessica H Hartman
- Nicholas School of the Environment, Duke University, Durham, NC, 27708, United States of America
| | - Christopher T Richie
- Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, 21224, United States of America
| | - Kacy L Gordon
- Department of Biology, Regeneration Next, Duke University, Durham, NC, 27708, United States of America
| | - Danielle F Mello
- Nicholas School of the Environment, Duke University, Durham, NC, 27708, United States of America
| | - Priscila Castillo
- Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, 21224, United States of America
| | - April Zhu
- Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, 21224, United States of America
| | - Yun Wang
- Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, 21224, United States of America
| | - Barry J Hoffer
- Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, 21224, United States of America
| | - David R Sherwood
- Department of Biology, Regeneration Next, Duke University, Durham, NC, 27708, United States of America
| | - Joel N Meyer
- Nicholas School of the Environment, Duke University, Durham, NC, 27708, United States of America
| | - Brandon K Harvey
- Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, 21224, United States of America.
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Gamma Entrainment Binds Higher-Order Brain Regions and Offers Neuroprotection. Neuron 2019; 102:929-943.e8. [PMID: 31076275 DOI: 10.1016/j.neuron.2019.04.011] [Citation(s) in RCA: 245] [Impact Index Per Article: 40.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2018] [Revised: 01/23/2019] [Accepted: 04/03/2019] [Indexed: 12/18/2022]
Abstract
Neuronal and synaptic loss is characteristic in many neurodegenerative diseases, such as frontotemporal dementia and Alzheimer's disease. Recently, we showed that inducing gamma oscillations with visual stimulation (gamma entrainment using sensory stimuli, or GENUS) reduced amyloid plaques and phosphorylated tau in multiple mouse models. Whether GENUS can affect neurodegeneration or cognitive performance remains unknown. Here, we demonstrate that GENUS can entrain gamma oscillations in the visual cortex, hippocampus, and prefrontal cortex in Tau P301S and CK-p25 mouse models of neurodegeneration. Tau P301S and CK-p25 mice subjected to chronic, daily GENUS from the early stages of neurodegeneration showed a preservation of neuronal and synaptic density across multiple brain areas and modified cognitive performance. Our transcriptomic and phosphoproteomic data suggest that chronic GENUS shifts neurons to a less degenerative state, improving synaptic function, enhancing neuroprotective factors, and reducing DNA damage in neurons while also reducing inflammatory response in microglia.
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Anttila JE, Pöyhönen S, Airavaara M. Secondary Pathology of the Thalamus after Focal Cortical Stroke in Rats is not Associated with Thermal or Mechanical Hypersensitivity and is Not Alleviated by Intra-Thalamic Post-Stroke Delivery of Recombinant CDNF or MANF. Cell Transplant 2019; 28:425-438. [PMID: 31037983 PMCID: PMC6628565 DOI: 10.1177/0963689719837915] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
A stroke affecting the somatosensory pathway can trigger central post-stroke pain
syndrome (CPSP). The symptoms often include hyperalgesia, which has also been described in
rodents after the direct damage of the thalamus. Previous studies have shown that
hemorrhagic stroke or ischemia caused by vasoconstriction in the thalamus induces
increased pain sensitivity. We investigated whether inducing secondary damage in the
thalamus by a cortical stroke causes similar pain hypersensitivity as has previously been
reported with direct ischemic injury. We induced a focal cortical ischemia-reperfusion
injury in male rats, quantified the amount of secondary neurodegeneration in the thalamus,
and measured whether the thalamic neurodegeneration is associated with thermal or
mechanical hypersensitivity. After one month, we observed extensive neuronal degeneration
and found approximately 40% decrease in the number of NeuN+ cells in the ipsilateral
thalamus. At the same time, there was a massive accumulation—a 30-fold increase—of
phagocytic cells in the ipsilateral thalamus. However, despite the evident damage in the
thalamus, we did not observe thermal or mechanical sensitization. Thus, thalamic
neurodegeneration after cortical ischemia-reperfusion does not induce CPSP-like symptoms
in rats, and these results suggest that direct ischemic damage is needed for CPSP
induction. Despite not observing hyperalgesia, we investigated whether administration of
cerebral dopamine neurotrophic factor (CDNF) and mesencephalic astrocyte-derived
neurotrophic factor (MANF) into the ipsilateral thalamus would reduce the secondary
damage. We gave a single injection (10 µg) of recombinant CDNF or MANF protein into the
thalamus at 7 days post-stroke. Both CDNF and MANF treatment promoted the functional
recovery but had no effect on the neuronal loss or the amount of phagocytic cells in the
thalamus.
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Affiliation(s)
- Jenni E. Anttila
- Institute of Biotechnology, HiLIFE, University of Helsinki, Helsinki,
Finland
| | - Suvi Pöyhönen
- Institute of Biotechnology, HiLIFE, University of Helsinki, Helsinki,
Finland
| | - Mikko Airavaara
- Institute of Biotechnology, HiLIFE, University of Helsinki, Helsinki,
Finland
- Mikko Airavaara, Institute of Biotechnology, HiLIFE,
University of Helsinki, P.O. Box 56, Helsinki 00014, Finland.
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Abstract
Neurotrophic factors (NTF) are a subgroup of growth factors that promote survival and
differentiation of neurons. Due to their neuroprotective and neurorestorative properties,
their therapeutic potential has been tested in various neurodegenerative diseases.
Bioavailability of NTFs in the target tissue remains a major challenge for NTF-based
therapies. Various intracerebral delivery approaches, both protein and gene
transfer-based, have been tested with varying outcomes. Three growth factors, glial
cell-line derived neurotrophic factor (GDNF), neurturin (NRTN) and platelet-derived growth
factor (PDGF-BB) have been tested in clinical trials in Parkinson’s disease (PD) during
the past 20 years. A new protein can now be added to this list, as cerebral dopamine
neurotrophic factor (CDNF) has recently entered clinical trials. Despite their misleading
names, CDNF, together with its closest relative mesencephalic astrocyte-derived
neurotrophic factor (MANF), form a novel family of unconventional NTF that are both
structurally and mechanistically distinct from other growth factors. CDNF and MANF are
localized mainly to the lumen of endoplasmic reticulum (ER) and their primary function
appears to be modulation of the unfolded protein response (UPR) pathway. Prolonged ER
stress, via the UPR signaling pathways, contributes to the pathogenesis in a number of
chronic degenerative diseases, and is an important target for therapeutic modulation.
Intraputamenally administered recombinant human CDNF has shown robust neurorestorative
effects in a number of small and large animal models of PD, and had a good safety profile
in preclinical toxicology studies. Intermittent monthly bilateral intraputamenal infusions
of CDNF are currently being tested in a randomized placebo-controlled phase I–II clinical
study in moderately advanced PD patients. Here, we review the history of growth
factor-based clinical trials in PD, and discuss how CDNF differs from the previously
tested growth factors.
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Affiliation(s)
- Henri J Huttunen
- 1 Herantis Pharma Plc, Espoo, Finland.,2 Neuroscience Center, HiLIFE, University of Helsinki, Helsinki, Finland
| | - Mart Saarma
- 3 Institute of Biotechnology, HiLIFE, University of Helsinki, Helsinki, Finland
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Liu J, Liu W, Yang H. Balancing Apoptosis and Autophagy for Parkinson's Disease Therapy: Targeting BCL-2. ACS Chem Neurosci 2019; 10:792-802. [PMID: 30400738 DOI: 10.1021/acschemneuro.8b00356] [Citation(s) in RCA: 96] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Apoptosis and autophagy are important intracellular processes that maintain organism homeostasis and promote survival. Autophagy selectively degrades damaged cellular organelles and protein aggregates, while apoptosis removes damaged or aged cells. Maintaining a balance between autophagy and apoptosis is critical for cell fate, especially for long-lived cells such as neurons. Conversely, their imbalance is associated with neurodegenerative diseases such as Parkinson's disease (PD), which is characterized by a progressive loss of dopaminergic neurons in the substantia nigra pars compacta. Restoring the balance between autophagy and apoptosis is a promising strategy for the treatment of PD. Some core proteins engage in cross talk between apoptosis and autophagy, including B cell lymphoma (BCL)-2 family members. This Review summarizes the role of BCL-2 members in the regulation of apoptosis and autophagy and discusses potential therapeutic approaches that target this balance for PD treatment.
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Affiliation(s)
- Jia Liu
- Department of Neurobiology School of
Basic Medical Sciences, Capital Medical University, Center of Parkinson’s
Disease Beijing Institute for Brain Disorders, Beijing Key Laboratory
of Neural Regeneration and Repair, Beijing Key Laboratory on Parkinson’s
Disease, Key Laboratory for Neurodegenerative Disease of the Ministry
of Education, Beijing 100069, China
| | - Weijing Liu
- Department of Neurobiology School of
Basic Medical Sciences, Capital Medical University, Center of Parkinson’s
Disease Beijing Institute for Brain Disorders, Beijing Key Laboratory
of Neural Regeneration and Repair, Beijing Key Laboratory on Parkinson’s
Disease, Key Laboratory for Neurodegenerative Disease of the Ministry
of Education, Beijing 100069, China
| | - Hui Yang
- Department of Neurobiology School of
Basic Medical Sciences, Capital Medical University, Center of Parkinson’s
Disease Beijing Institute for Brain Disorders, Beijing Key Laboratory
of Neural Regeneration and Repair, Beijing Key Laboratory on Parkinson’s
Disease, Key Laboratory for Neurodegenerative Disease of the Ministry
of Education, Beijing 100069, China
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Xu S, Di Z, He Y, Wang R, Ma Y, Sun R, Li J, Wang T, Shen Y, Fang S, Feng L, Shen Y. Mesencephalic astrocyte-derived neurotrophic factor (MANF) protects against Aβ toxicity via attenuating Aβ-induced endoplasmic reticulum stress. J Neuroinflammation 2019; 16:35. [PMID: 30760285 PMCID: PMC6373169 DOI: 10.1186/s12974-019-1429-0] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2018] [Accepted: 02/03/2019] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Extracellular accumulation of amyloid β-peptide (Aβ) is one of pathological hallmarks of Alzheimer's disease (AD) and contributes to the neuronal loss. Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an endoplasmic reticulum (ER) stress-inducible neurotrophic factor. Many groups, including ours, have proved that MANF rescues neuronal loss in several neurological disorders, such as Parkinson's disease and cerebral ischemia. However, whether MANF exerts its protective effect against Aβ neurotoxicity in AD remains unknown. METHODS In the present study, the characteristic expressions of MANF in Aβ1-42-treated neuronal cells as well as in the brains of APP/PS1 transgenic mice were analyzed by immunofluorescence staining, qPCR, and Western blot. The effects of MANF overexpression, MANF knockdown, or recombination human MANF protein (rhMANF) on neuron viability, apoptosis, and the expression of ER stress-related proteins following Aβ1-42 exposure were also investigated. RESULTS The results showed the increased expressions of MANF, as well as ER stress markers immunoglobulin-binding protein (BiP) and C/EBP homologous protein (CHOP), in the brains of the APP/PS1 transgenic mice and Aβ1-42-treated neuronal cells. MANF overexpression or rhMANF treatment partially protected against Aβ1-42-induced neuronal cell death, associated with marked decrease of cleaved caspase-3, whereas MANF knockdown with siRNA aggravated Aβ1-42 cytotoxicity including caspase-3 activation. Further study demonstrated that the expressions of BiP, ATF6, phosphorylated-IRE1, XBP1s, phosphorylated-eIF2α, ATF4, and CHOP were significantly downregulated by MANF overexpression or rhMANF treatment in neuronal cells following Aβ1-42 exposure, whereas knockdown of MANF has the opposite effect. CONCLUSIONS These findings demonstrate that MANF may exert neuroprotective effects against Aβ-induced neurotoxicity through attenuating ER stress, suggesting that an applicability of MANF as a therapeutic candidate for AD.
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Affiliation(s)
- Shengchun Xu
- School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, China
| | - Zemin Di
- School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, China.,Biopharmaceutical Research Institute, Anhui Medical University, Hefei, 230032, China.,Institute of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, China
| | - Yufeng He
- School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, China.,Biopharmaceutical Research Institute, Anhui Medical University, Hefei, 230032, China.,Institute of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, China
| | - Runjie Wang
- School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, China.,Biopharmaceutical Research Institute, Anhui Medical University, Hefei, 230032, China.,Institute of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, China
| | - Yuyang Ma
- School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, China.,Biopharmaceutical Research Institute, Anhui Medical University, Hefei, 230032, China.,Institute of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, China
| | - Rui Sun
- School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, China.,Biopharmaceutical Research Institute, Anhui Medical University, Hefei, 230032, China
| | - Jing Li
- School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, China.,Biopharmaceutical Research Institute, Anhui Medical University, Hefei, 230032, China
| | - Tao Wang
- School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, China
| | - Yujun Shen
- School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, China.,Biopharmaceutical Research Institute, Anhui Medical University, Hefei, 230032, China.,Institute of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, China
| | - Shengyun Fang
- School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, China.,Biopharmaceutical Research Institute, Anhui Medical University, Hefei, 230032, China.,Center for Biomedical Engineering and Technology, University of Maryland, Baltimore, MD, USA
| | - Lijie Feng
- School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, China. .,Biopharmaceutical Research Institute, Anhui Medical University, Hefei, 230032, China. .,Institute of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, China.
| | - Yuxian Shen
- School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, China. .,Biopharmaceutical Research Institute, Anhui Medical University, Hefei, 230032, China. .,Institute of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, China.
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Yan Y, Rato C, Rohland L, Preissler S, Ron D. MANF antagonizes nucleotide exchange by the endoplasmic reticulum chaperone BiP. Nat Commun 2019; 10:541. [PMID: 30710085 PMCID: PMC6358605 DOI: 10.1038/s41467-019-08450-4] [Citation(s) in RCA: 64] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2018] [Accepted: 01/11/2019] [Indexed: 12/24/2022] Open
Abstract
Despite its known role as a secreted neuroprotectant, much of the mesencephalic astrocyte-derived neurotrophic factor (MANF) is retained in the endoplasmic reticulum (ER) of producer cells. There, by unknown mechanisms, MANF plays a role in protein folding homeostasis in complex with the ER-localized Hsp70 chaperone BiP. Here we report that the SAF-A/B, Acinus, and PIAS (SAP) domain of MANF selectively associates with the nucleotide binding domain (NBD) of ADP-bound BiP. In crystal structures the SAP domain engages the cleft between NBD subdomains Ia and IIa, stabilizing the ADP-bound conformation and clashing with the interdomain linker that occupies this site in ATP-bound BiP. MANF inhibits both ADP release from BiP and ATP binding to BiP, and thereby client release. Cells lacking MANF have fewer ER stress-induced BiP-containing high molecular weight complexes. These findings suggest that MANF contributes to protein folding homeostasis as a nucleotide exchange inhibitor that stabilizes certain BiP-client complexes.
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Affiliation(s)
- Yahui Yan
- Cambridge Institute for Medical Research, University of Cambridge, Cambridge, CB2 0XY, UK
| | - Claudia Rato
- Cambridge Institute for Medical Research, University of Cambridge, Cambridge, CB2 0XY, UK
| | - Lukas Rohland
- Cambridge Institute for Medical Research, University of Cambridge, Cambridge, CB2 0XY, UK.,Center for Molecular Biology (ZMBH) of Heidelberg University, Heidelberg, Germany
| | - Steffen Preissler
- Cambridge Institute for Medical Research, University of Cambridge, Cambridge, CB2 0XY, UK.
| | - David Ron
- Cambridge Institute for Medical Research, University of Cambridge, Cambridge, CB2 0XY, UK.
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48
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Bell PA, Dennis EP, Hartley CL, Jackson RM, Porter A, Boot-Handford RP, Pirog KA, Briggs MD. Mesencephalic astrocyte-derived neurotropic factor is an important factor in chondrocyte ER homeostasis. Cell Stress Chaperones 2019; 24:159-173. [PMID: 30543055 PMCID: PMC6363614 DOI: 10.1007/s12192-018-0953-7] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2018] [Revised: 11/21/2018] [Accepted: 11/23/2018] [Indexed: 12/12/2022] Open
Abstract
Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an endoplasmic reticulum (ER) resident protein that can be secreted due to an imperfect KDEL motif. MANF plays a cytoprotective role in several soft tissues and is upregulated in conditions resulting from intracellular retention of mutant protein, including two skeletal diseases, metaphyseal chondrodysplasia, Schmid type (MCDS) and multiple epiphyseal dysplasia (MED). The role of MANF in skeletal tissue homeostasis is currently unknown. Interestingly, cartilage-specific deletion of Manf in a mouse model of MED resulted in increased disease severity, suggesting its upregulation may be chondroprotective. Treatment of MED chondrocytes with exogenous MANF led to a decrease in the cellular levels of BiP (GRP78), confirming MANF's potential to modulate ER stress responses. However, it did not alleviate the intracellular retention of mutant matrilin-3, suggesting that it is the intracellular MANF that is of importance in the pathobiology of skeletal dysplasias. The Col2Cre-driven deletion of Manf from mouse cartilage resulted in a chondrodysplasia-like phenotype. Interestingly, ablation of MANF in cartilage did not have extracellular consequences but led to an upregulation of several ER-resident chaperones including BiP. This apparent induction of ER stress in turn led to dysregulated chondrocyte apoptosis and decreased proliferation, resulting in reduced long bone growth. We have previously shown that ER stress is an underlying disease mechanism for several skeletal dysplasias. The cartilage-specific deletion of Manf described in this study phenocopies our previously published chondrodysplasia models, further confirming that ER stress itself is sufficient to disrupt skeletal growth and thus represents a potential therapeutic target.
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Affiliation(s)
- P A Bell
- Institute of Genetic Medicine, International Centre for Life, Newcastle University, Newcastle Upon Tyne, NE1 3BZ, UK
- Centre for Blood Research, University of British Columbia, Vancouver, BC, V6T 1Z3, Canada
| | - E P Dennis
- Institute of Genetic Medicine, International Centre for Life, Newcastle University, Newcastle Upon Tyne, NE1 3BZ, UK
- Wellcome Trust Centre for Cell-Matrix Research, University of Manchester, Oxford Road, Manchester, M13 9PT, UK
| | - C L Hartley
- Wellcome Trust Centre for Cell-Matrix Research, University of Manchester, Oxford Road, Manchester, M13 9PT, UK
- Genomic Diagnostics Laboratory, Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, Manchester, M13 9WL, UK
| | - R M Jackson
- Institute of Genetic Medicine, International Centre for Life, Newcastle University, Newcastle Upon Tyne, NE1 3BZ, UK
| | - A Porter
- Newcastle University Protein and Proteome Analysis Facility, Newcastle University, Newcastle Upon Tyne, NE1 7RU, UK
| | - R P Boot-Handford
- Wellcome Trust Centre for Cell-Matrix Research, University of Manchester, Oxford Road, Manchester, M13 9PT, UK
| | - K A Pirog
- Institute of Genetic Medicine, International Centre for Life, Newcastle University, Newcastle Upon Tyne, NE1 3BZ, UK.
| | - M D Briggs
- Institute of Genetic Medicine, International Centre for Life, Newcastle University, Newcastle Upon Tyne, NE1 3BZ, UK
- Wellcome Trust Centre for Cell-Matrix Research, University of Manchester, Oxford Road, Manchester, M13 9PT, UK
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Zhang Y, Xiang Y, Wang X, Zhu L, Li H, Wang S, Pan X, Zhao H. Cerebral dopamine neurotrophic factor protects microglia by combining with AKT and by regulating FoxO1/mTOR signaling during neuroinflammation. Biomed Pharmacother 2019; 109:2278-2284. [DOI: 10.1016/j.biopha.2018.11.028] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2018] [Revised: 11/06/2018] [Accepted: 11/06/2018] [Indexed: 01/13/2023] Open
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50
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Yang S, Li S, Li XJ. MANF: A New Player in the Control of Energy Homeostasis, and Beyond. Front Physiol 2018; 9:1725. [PMID: 30555354 PMCID: PMC6282101 DOI: 10.3389/fphys.2018.01725] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2018] [Accepted: 11/15/2018] [Indexed: 01/06/2023] Open
Abstract
All human behaviors, including the control of energy homeostasis, are ultimately mediated by neuronal activities in the brain. Neurotrophic factors represent a protein family that plays important roles in regulating neuronal development, function, and survival. It has been well established that canonical neurotrophic factors, such as brain-derived neurotrophic factor (BDNF) and ciliary neurotrophic factor (CNTF), play important roles in the central regulation of energy homeostasis. Recently, a class of non-canonical neurotrophic factors, represented by mesencephalic astrocyte-derived neurotrophic factor (MANF), has been discovered. MANF is structurally and functionally distinct from those canonical neurotrophic factors, hence raising the issue of MANF being non-canonical. Nonetheless, emerging evidence suggests that MANF is critically involved in many neuronal activities. Here, we review our current understanding about the functions of MANF in the brain, with a primary focus on the control of energy homeostasis.
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Affiliation(s)
- Su Yang
- Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, United States
| | - Shihua Li
- GHM Institute of CNS Regeneration, Jinan University Guangzhou, China
| | - Xiao-Jiang Li
- Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, United States
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