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Tanu, Chaturvedi M, Fatima S, Yadav SS, Padhy PK, Tiwari S, Seth K, Chaturvedi RK, Priya S. Expression analysis of molecular chaperones associated with disaggregation complex in rotenone-induced Parkinsonian rat model. Int J Biochem Cell Biol 2025; 181:106752. [PMID: 39952347 DOI: 10.1016/j.biocel.2025.106752] [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: 08/31/2024] [Revised: 01/30/2025] [Accepted: 02/11/2025] [Indexed: 02/17/2025]
Abstract
Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the aberrant aggregation and phosphorylation (ser129) of α-synuclein (α-syn, a presynaptic protein) which leads to the formation of pathogenic Lewy bodies. A critical factor in the pathogenesis of PD is the disruption of the cellular protein quality control system, where molecular chaperones and their co-chaperones are integral for mitigating proteotoxic stress. Although the role of molecular chaperones in PD and other protein aggregation diseases has been extensively investigated, the in vivo investigation of disaggregation chaperones, including HSP70, HSP105, and co-chaperone DNAJBs, remains relatively limited. The present study aims to elucidate the expression dynamics of the disaggregation molecular chaperones within the substantia nigra pars compacta of the rotenone-induced Parkinsonian rat model and its association with α-syn aggregation. The rotenone-treated rats exhibited significant behavioural symptoms, α-syn aggregation and degeneration of dopaminergic neurons, confirming the development of Parkinsonism. Significant upregulation of α-syn expression/phosphorylation and co-localization in TH+ve neurons in the SNpc of treated rats was observed. Further, the gene and protein analysis of HSP70, DNAJB6, and HSP105 were found to be upregulated and TH+ve neurons showed their co-localization with p-α-synser129 expression. The total proteomic analysis of SNpc correlated the altered cellular processes with cellular homeostasis imbalance. The observations of the present study provide an in vivo analysis of disaggregation-associated molecular chaperones in Parkinsonian or α-syn related conditions. The study can be helpful for further manipulation in the expression or activity of disaggregation-related chaperones for advanced therapeutic strategies and mechanistic studies in protein aggregation-associated diseases.
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Affiliation(s)
- Tanu
- Systems Toxicology Group, FEST Division, CSIR - Indian Institute of Toxicology Research, Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow, Uttar Pradesh 226001, India
| | - Minal Chaturvedi
- Systems Toxicology Group, FEST Division, CSIR - Indian Institute of Toxicology Research, Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow, Uttar Pradesh 226001, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Siraj Fatima
- Systems Toxicology Group, FEST Division, CSIR - Indian Institute of Toxicology Research, Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow, Uttar Pradesh 226001, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Smriti Singh Yadav
- Systems Toxicology Group, FEST Division, CSIR - Indian Institute of Toxicology Research, Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow, Uttar Pradesh 226001, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Prabeen Kumar Padhy
- Systems Toxicology Group, FEST Division, CSIR - Indian Institute of Toxicology Research, Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow, Uttar Pradesh 226001, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India; Food Toxicology Group, FEST Division, CSIR - Indian Institute of Toxicology Research, Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow, Uttar Pradesh 226001, India
| | - Saurabh Tiwari
- Systems Toxicology Group, FEST Division, CSIR - Indian Institute of Toxicology Research, Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow, Uttar Pradesh 226001, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Kavita Seth
- Systems Toxicology Group, FEST Division, CSIR - Indian Institute of Toxicology Research, Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow, Uttar Pradesh 226001, India
| | - Rajnish K Chaturvedi
- Systems Toxicology Group, FEST Division, CSIR - Indian Institute of Toxicology Research, Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow, Uttar Pradesh 226001, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Smriti Priya
- Systems Toxicology Group, FEST Division, CSIR - Indian Institute of Toxicology Research, Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow, Uttar Pradesh 226001, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India.
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Ou L, Setegne MT, Elliot J, Shen F, Dassama LMK. Protein-Based Degraders: From Chemical Biology Tools to Neo-Therapeutics. Chem Rev 2025; 125:2120-2183. [PMID: 39818743 PMCID: PMC11870016 DOI: 10.1021/acs.chemrev.4c00595] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2024] [Revised: 12/26/2024] [Accepted: 12/30/2024] [Indexed: 01/19/2025]
Abstract
The nascent field of targeted protein degradation (TPD) could revolutionize biomedicine due to the ability of degrader molecules to selectively modulate disease-relevant proteins. A key limitation to the broad application of TPD is its dependence on small-molecule ligands to target proteins of interest. This leaves unstructured proteins or those lacking defined cavities for small-molecule binding out of the scope of many TPD technologies. The use of proteins, peptides, and nucleic acids (otherwise known as "biologics") as the protein-targeting moieties in degraders addresses this limitation. In the following sections, we provide a comprehensive and critical review of studies that have used proteins and peptides to mediate the degradation and hence the functional control of otherwise challenging disease-relevant protein targets. We describe existing platforms for protein/peptide-based ligand identification and the drug delivery systems that might be exploited for the delivery of biologic-based degraders. Throughout the Review, we underscore the successes, challenges, and opportunities of using protein-based degraders as chemical biology tools to spur discoveries, elucidate mechanisms, and act as a new therapeutic modality.
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Affiliation(s)
- Lisha Ou
- Department
of Chemistry, Stanford University, Stanford, California 94305, United States
- Sarafan
ChEM-H Institute, Stanford University, Stanford, California 94305, United States
| | - Mekedlawit T. Setegne
- Department
of Chemistry, Stanford University, Stanford, California 94305, United States
- Sarafan
ChEM-H Institute, Stanford University, Stanford, California 94305, United States
| | - Jeandele Elliot
- Department
of Chemical Engineering, Stanford University, Stanford, California 94305, United States
| | - Fangfang Shen
- Department
of Chemistry, Stanford University, Stanford, California 94305, United States
| | - Laura M. K. Dassama
- Department
of Chemistry, Stanford University, Stanford, California 94305, United States
- Sarafan
ChEM-H Institute, Stanford University, Stanford, California 94305, United States
- Department
of Microbiology & Immunology, Stanford
School of Medicine, Stanford, California 94305, United States
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3
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Pan Z, Huang X, Liu M, Jiang X, He G. Research Advances in Chaperone-Mediated Autophagy (CMA) and CMA-Based Protein Degraders. J Med Chem 2025; 68:2314-2332. [PMID: 39818775 DOI: 10.1021/acs.jmedchem.4c02681] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2025]
Abstract
Molecular mechanisms of chaperone-mediated autophagy (CMA) constitute essential regulatory elements in cellular homeostasis, encompassing protein quality control, metabolic regulation, cellular signaling cascades, and immunological functions. Perturbations in CMA functionality have been causally associated with various pathological conditions, including neurodegenerative pathologies and neoplastic diseases. Recent advances in targeted protein degradation (TPD) methodologies have demonstrated that engineered degraders incorporating KFERQ-like motifs can facilitate lysosomal translocation and subsequent proteolysis of noncanonical substrates, offering novel therapeutic interventions for both oncological and neurodegenerative disorders. This comprehensive review elucidates the molecular mechanisms, physiological significance, and pathological implications of CMA pathways. Additionally, it provides a critical analysis of contemporary developments in CMA-based degrader technologies, with particular emphasis on their structural determinants, mechanistic principles, and therapeutic applications. The discourse extends to current technical limitations in CMA investigation and identifies key obstacles that must be addressed to advance the development of CMA-targeting therapeutic agents.
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Affiliation(s)
- Zhaoping Pan
- Department of Dermatology & Venerology, West China Hospital, Sichuan University, Chengdu 610041, China
- Laboratory of Dermatology, Clinical Institute of Inflammation and Immunology, Frontiers Science Center for Disease-related Molecular Network, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Xiaowei Huang
- Department of Dermatology & Venerology, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Mingxia Liu
- Department of Dermatology & Venerology, West China Hospital, Sichuan University, Chengdu 610041, China
- Laboratory of Dermatology, Clinical Institute of Inflammation and Immunology, Frontiers Science Center for Disease-related Molecular Network, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Xian Jiang
- Department of Dermatology & Venerology, West China Hospital, Sichuan University, Chengdu 610041, China
- Laboratory of Dermatology, Clinical Institute of Inflammation and Immunology, Frontiers Science Center for Disease-related Molecular Network, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Gu He
- Department of Dermatology & Venerology, West China Hospital, Sichuan University, Chengdu 610041, China
- Laboratory of Dermatology, Clinical Institute of Inflammation and Immunology, Frontiers Science Center for Disease-related Molecular Network, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
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Wang Y, Liu J, Wang H, Jiang P, Cao L, Lu S, Zhang S, Yang R, Feng H, Cao L, Song X. Multiple regulatory mechanisms, functions and therapeutic potential of chaperone-mediated autophagy. Theranostics 2025; 15:2778-2793. [PMID: 40083922 PMCID: PMC11898275 DOI: 10.7150/thno.107761] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2024] [Accepted: 01/25/2025] [Indexed: 03/16/2025] Open
Abstract
Autophagy refers to the proteolytic degradation of cytoplasmic components by lysosomes, and includes three defined types: macroautophagy, chaperone-mediated autophagy (CMA), and microautophagy. Although the regulatory pathways of macroautophagy are well defined, how CMA is accurately regulated remains less understood. In recent years, emerging evidence has suggested that chaperone-mediated autophagy is regulated by multiple mechanisms at nucleic acid and protein levels. In this review, we summarized recent progress on multiple regulatory mechanisms and functions concerning CMA, as well as novel treatments targeting specific regulation sites.
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Affiliation(s)
- Yuhan Wang
- The College of Basic Medical Science, Health Sciences Institute, China Medical University, Shenyang, Liaoning Province 110122, China
- Key Laboratory of Cell Biology of Ministry of Public Health, Key Laboratory of Medical Cell Biology of Ministry of Education, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors of Ministry of Education, Liaoning Province Collaborative Innovation Center of Aging Related Disease Diagnosis and Treatment and Prevention, China Medical University, Shenyang, Liaoning Province 110122, China
| | - Jingwei Liu
- The College of Basic Medical Science, Health Sciences Institute, China Medical University, Shenyang, Liaoning Province 110122, China
- Key Laboratory of Cell Biology of Ministry of Public Health, Key Laboratory of Medical Cell Biology of Ministry of Education, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors of Ministry of Education, Liaoning Province Collaborative Innovation Center of Aging Related Disease Diagnosis and Treatment and Prevention, China Medical University, Shenyang, Liaoning Province 110122, China
| | - Hao Wang
- Department of Gastroenterology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Pengcheng Jiang
- The College of Basic Medical Science, Health Sciences Institute, China Medical University, Shenyang, Liaoning Province 110122, China
- Key Laboratory of Cell Biology of Ministry of Public Health, Key Laboratory of Medical Cell Biology of Ministry of Education, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors of Ministry of Education, Liaoning Province Collaborative Innovation Center of Aging Related Disease Diagnosis and Treatment and Prevention, China Medical University, Shenyang, Liaoning Province 110122, China
| | - Liangzi Cao
- The College of Basic Medical Science, Health Sciences Institute, China Medical University, Shenyang, Liaoning Province 110122, China
- Key Laboratory of Cell Biology of Ministry of Public Health, Key Laboratory of Medical Cell Biology of Ministry of Education, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors of Ministry of Education, Liaoning Province Collaborative Innovation Center of Aging Related Disease Diagnosis and Treatment and Prevention, China Medical University, Shenyang, Liaoning Province 110122, China
| | - Songming Lu
- The College of Basic Medical Science, Health Sciences Institute, China Medical University, Shenyang, Liaoning Province 110122, China
- Key Laboratory of Cell Biology of Ministry of Public Health, Key Laboratory of Medical Cell Biology of Ministry of Education, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors of Ministry of Education, Liaoning Province Collaborative Innovation Center of Aging Related Disease Diagnosis and Treatment and Prevention, China Medical University, Shenyang, Liaoning Province 110122, China
| | - Siyi Zhang
- The College of Basic Medical Science, Health Sciences Institute, China Medical University, Shenyang, Liaoning Province 110122, China
- Key Laboratory of Cell Biology of Ministry of Public Health, Key Laboratory of Medical Cell Biology of Ministry of Education, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors of Ministry of Education, Liaoning Province Collaborative Innovation Center of Aging Related Disease Diagnosis and Treatment and Prevention, China Medical University, Shenyang, Liaoning Province 110122, China
| | - Ruohan Yang
- The College of Basic Medical Science, Health Sciences Institute, China Medical University, Shenyang, Liaoning Province 110122, China
- Key Laboratory of Cell Biology of Ministry of Public Health, Key Laboratory of Medical Cell Biology of Ministry of Education, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors of Ministry of Education, Liaoning Province Collaborative Innovation Center of Aging Related Disease Diagnosis and Treatment and Prevention, China Medical University, Shenyang, Liaoning Province 110122, China
| | - Hao Feng
- Department of Ophthalmology, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, 110001, China
| | - Liu Cao
- The College of Basic Medical Science, Health Sciences Institute, China Medical University, Shenyang, Liaoning Province 110122, China
- Key Laboratory of Cell Biology of Ministry of Public Health, Key Laboratory of Medical Cell Biology of Ministry of Education, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors of Ministry of Education, Liaoning Province Collaborative Innovation Center of Aging Related Disease Diagnosis and Treatment and Prevention, China Medical University, Shenyang, Liaoning Province 110122, China
| | - Xiaoyu Song
- The College of Basic Medical Science, Health Sciences Institute, China Medical University, Shenyang, Liaoning Province 110122, China
- Key Laboratory of Cell Biology of Ministry of Public Health, Key Laboratory of Medical Cell Biology of Ministry of Education, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors of Ministry of Education, Liaoning Province Collaborative Innovation Center of Aging Related Disease Diagnosis and Treatment and Prevention, China Medical University, Shenyang, Liaoning Province 110122, China
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5
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Qian S, Long Y, Tan G, Li X, Xiang B, Tao Y, Xie Z, Zhang X. Programmed cell death: molecular mechanisms, biological functions, diseases, and therapeutic targets. MedComm (Beijing) 2024; 5:e70024. [PMID: 39619229 PMCID: PMC11604731 DOI: 10.1002/mco2.70024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2024] [Revised: 11/02/2024] [Accepted: 11/11/2024] [Indexed: 01/12/2025] Open
Abstract
Programmed cell death represents a precisely regulated and active cellular demise, governed by a complex network of specific genes and proteins. The identification of multiple forms of programmed cell death has significantly advanced the understanding of its intricate mechanisms, as demonstrated in recent studies. A thorough grasp of these processes is essential across various biological disciplines and in the study of diseases. Nonetheless, despite notable progress, the exploration of the relationship between programmed cell death and disease, as well as its clinical application, are still in a nascent stage. Therefore, further exploration of programmed cell death and the development of corresponding therapeutic methods and strategies holds substantial potential. Our review provides a detailed examination of the primary mechanisms behind apoptosis, autophagy, necroptosis, pyroptosis, and ferroptosis. Following this, the discussion delves into biological functions and diseases associated dysregulated programmed cell death. Finally, we highlight existing and potential therapeutic targets and strategies focused on cancers and neurodegenerative diseases. This review aims to summarize the latest insights on programmed cell death from mechanisms to diseases and provides a more reliable approach for clinical transformation.
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Affiliation(s)
- Shen'er Qian
- Department of Otolaryngology Head and Neck SurgeryThe Third Xiangya Hospital, Central South UniversityChangshaHunanChina
| | - Yao Long
- Cancer Research InstituteSchool of Basic MedicineCentral South UniversityChangshaHunanChina
- Department of PathologyXiangya Hospital, Central South UniversityChangshaHunanChina
| | - Guolin Tan
- Department of Otolaryngology Head and Neck SurgeryThe Third Xiangya Hospital, Central South UniversityChangshaHunanChina
| | - Xiaoguang Li
- Department of Otolaryngology Head and Neck SurgeryShanghai Ninth People's Hospital, Shanghai Jiao Tong University School of MedicineShanghaiChina
- Ear InstituteShanghai Jiao Tong University School of Medicine, Shanghai Key LabShanghaiChina
| | - Bo Xiang
- Cancer Research InstituteSchool of Basic MedicineCentral South UniversityChangshaHunanChina
- Furong LaboratoryCentral South UniversityChangshaHunanChina
| | - Yongguang Tao
- Cancer Research InstituteSchool of Basic MedicineCentral South UniversityChangshaHunanChina
| | - Zuozhong Xie
- Department of Otolaryngology Head and Neck SurgeryThe Second Xiangya HospitalCentral South UniversityChangshaHunanChina
| | - Xiaowei Zhang
- Department of Otolaryngology Head and Neck SurgeryThe Third Xiangya Hospital, Central South UniversityChangshaHunanChina
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6
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Huang X, Wu F, Ye J, Wang L, Wang X, Li X, He G. Expanding the horizons of targeted protein degradation: A non-small molecule perspective. Acta Pharm Sin B 2024; 14:2402-2427. [PMID: 38828146 PMCID: PMC11143490 DOI: 10.1016/j.apsb.2024.01.010] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Revised: 12/22/2023] [Accepted: 01/16/2024] [Indexed: 06/05/2024] Open
Abstract
Targeted protein degradation (TPD) represented by proteolysis targeting chimeras (PROTACs) marks a significant stride in drug discovery. A plethora of innovative technologies inspired by PROTAC have not only revolutionized the landscape of TPD but have the potential to unlock functionalities beyond degradation. Non-small-molecule-based approaches play an irreplaceable role in this field. A wide variety of agents spanning a broad chemical spectrum, including peptides, nucleic acids, antibodies, and even vaccines, which not only prove instrumental in overcoming the constraints of conventional small molecule entities but also provided rapidly renewing paradigms. Herein we summarize the burgeoning non-small molecule technological platforms inspired by PROTACs, including three major trajectories, to provide insights for the design strategies based on novel paradigms.
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Affiliation(s)
- Xiaowei Huang
- Department of Pharmacy and Department of Dermatology & Venerology, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Fengbo Wu
- Department of Pharmacy and Department of Dermatology & Venerology, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Jing Ye
- Department of Pharmacy and Department of Dermatology & Venerology, West China Hospital, Sichuan University, Chengdu 610041, China
- Laboratory of Dermatology, Clinical Institute of Inflammation and Immunology, Frontiers Science Center for Disease-Related Molecular Network and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Lian Wang
- Department of Pharmacy and Department of Dermatology & Venerology, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Xiaoyun Wang
- Department of Pharmacy and Department of Dermatology & Venerology, West China Hospital, Sichuan University, Chengdu 610041, China
- Laboratory of Dermatology, Clinical Institute of Inflammation and Immunology, Frontiers Science Center for Disease-Related Molecular Network and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Xiang Li
- Department of Urology, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Gu He
- Department of Pharmacy and Department of Dermatology & Venerology, West China Hospital, Sichuan University, Chengdu 610041, China
- Laboratory of Dermatology, Clinical Institute of Inflammation and Immunology, Frontiers Science Center for Disease-Related Molecular Network and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
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7
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Jia Q, Li J, Guo X, Li Y, Wu Y, Peng Y, Fang Z, Zhang X. Neuroprotective effects of chaperone-mediated autophagy in neurodegenerative diseases. Neural Regen Res 2024; 19:1291-1298. [PMID: 37905878 PMCID: PMC11467915 DOI: 10.4103/1673-5374.385848] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Revised: 05/30/2023] [Accepted: 07/17/2023] [Indexed: 11/02/2023] Open
Abstract
ABSTRACT Chaperone-mediated autophagy is one of three types of autophagy and is characterized by the selective degradation of proteins. Chaperone-mediated autophagy contributes to energy balance and helps maintain cellular homeostasis, while providing nutrients and support for cell survival. Chaperone-mediated autophagy activity can be detected in almost all cells, including neurons. Owing to the extreme sensitivity of neurons to their environmental changes, maintaining neuronal homeostasis is critical for neuronal growth and survival. Chaperone-mediated autophagy dysfunction is closely related to central nervous system diseases. It has been shown that neuronal damage and cell death are accompanied by chaperone-mediated autophagy dysfunction. Under certain conditions, regulation of chaperone-mediated autophagy activity attenuates neurotoxicity. In this paper, we review the changes in chaperone-mediated autophagy in neurodegenerative diseases, brain injury, glioma, and autoimmune diseases. We also summarize the most recent research progress on chaperone-mediated autophagy regulation and discuss the potential of chaperone-mediated autophagy as a therapeutic target for central nervous system diseases.
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Affiliation(s)
- Qi Jia
- Department of Anesthesiology and Perioperative Medicine and Department of Intensive Care Unit, Xijing Hospital, The Fourth Military Medical University, Xi’an, Shaanxi Province, China
| | - Jin Li
- Department of Anesthesiology and Perioperative Medicine and Department of Intensive Care Unit, Xijing Hospital, The Fourth Military Medical University, Xi’an, Shaanxi Province, China
- Department of Critical Care Medicine, Air Force Medical Center, Beijing, China
| | - Xiaofeng Guo
- Department of Anesthesiology and Perioperative Medicine and Department of Intensive Care Unit, Xijing Hospital, The Fourth Military Medical University, Xi’an, Shaanxi Province, China
| | - Yi Li
- Department of Anesthesiology and Perioperative Medicine and Department of Intensive Care Unit, Xijing Hospital, The Fourth Military Medical University, Xi’an, Shaanxi Province, China
| | - You Wu
- Department of Anesthesiology and Perioperative Medicine and Department of Intensive Care Unit, Xijing Hospital, The Fourth Military Medical University, Xi’an, Shaanxi Province, China
| | - Yuliang Peng
- Department of Anesthesiology and Perioperative Medicine and Department of Intensive Care Unit, Xijing Hospital, The Fourth Military Medical University, Xi’an, Shaanxi Province, China
| | - Zongping Fang
- Department of Anesthesiology and Perioperative Medicine and Department of Intensive Care Unit, Xijing Hospital, The Fourth Military Medical University, Xi’an, Shaanxi Province, China
- Translational Research Institute of Brain and Brain-Like Intelligence, Shanghai Fourth People’s Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Xijing Zhang
- Department of Anesthesiology and Perioperative Medicine and Department of Intensive Care Unit, Xijing Hospital, The Fourth Military Medical University, Xi’an, Shaanxi Province, China
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8
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Andrikopoulos N, Tang H, Wang Y, Liang X, Li Y, Davis TP, Ke PC. Exploring Peptido-Nanocomposites in the Context of Amyloid Diseases. Angew Chem Int Ed Engl 2024; 63:e202309958. [PMID: 37943171 DOI: 10.1002/anie.202309958] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Revised: 10/27/2023] [Accepted: 11/09/2023] [Indexed: 11/10/2023]
Abstract
Therapeutic peptides are a major class of pharmaceutical drugs owing to their target-binding specificity as well as their versatility in inhibiting aberrant protein-protein interactions associated with human pathologies. Within the realm of amyloid diseases, the use of peptides and peptidomimetics tailor-designed to overcome amyloidogenesis has been an active research endeavor since the late 90s. In more recent years, incorporating nanoparticles for enhancing the biocirculation and delivery of peptide drugs has emerged as a frontier in nanomedicine, and nanoparticles have further demonstrated a potency against amyloid aggregation and cellular inflammation to rival strategies employing small molecules, peptides, and antibodies. Despite these efforts, however, a fundamental understanding of the chemistry, characteristics and function of peptido-nanocomposites is lacking, and a systematic analysis of such strategy for combating a range of amyloid pathogeneses is missing. Here we review the history, principles and evolving chemistry of constructing peptido-nanocomposites from bottom up and discuss their future application against amyloid diseases that debilitate a significant portion of the global population.
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Affiliation(s)
- Nicholas Andrikopoulos
- Nanomedicine Center, The Great Bay Area National Institute for Nanotechnology Innovation, 136 Kaiyuan Avenue, Guangzhou, 510700, China
- Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3052, Australia
| | - Huayuan Tang
- College of Mechanics and Materials, Hohai University, Nanjing, 211100, China
- Department of Physics and Astronomy, Clemson University, Clemson, SC 29634, USA
| | - Yue Wang
- Nanomedicine Center, The Great Bay Area National Institute for Nanotechnology Innovation, 136 Kaiyuan Avenue, Guangzhou, 510700, China
- School of Biomedical Sciences and Engineering, Guangzhou International Campus, South China University of Technology, Guangzhou 510006, China
| | - Xiufang Liang
- Nanomedicine Center, The Great Bay Area National Institute for Nanotechnology Innovation, 136 Kaiyuan Avenue, Guangzhou, 510700, China
- School of Biomedical Sciences and Engineering, Guangzhou International Campus, South China University of Technology, Guangzhou 510006, China
| | - Yuhuan Li
- Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3052, Australia
- Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Fudan University, Shanghai, 200032, China
| | - Thomas P Davis
- Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3052, Australia
- Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, Qld 4072, Australia
| | - Pu Chun Ke
- Nanomedicine Center, The Great Bay Area National Institute for Nanotechnology Innovation, 136 Kaiyuan Avenue, Guangzhou, 510700, China
- Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3052, Australia
- Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, Qld 4072, Australia
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9
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Hu M, Ying X, Zheng M, Wang C, Li Q, Gu L, Zhang X. Therapeutic potential of natural products against Alzheimer's disease via autophagic removal of Aβ. Brain Res Bull 2024; 206:110835. [PMID: 38043648 DOI: 10.1016/j.brainresbull.2023.110835] [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: 08/22/2023] [Revised: 11/17/2023] [Accepted: 11/30/2023] [Indexed: 12/05/2023]
Abstract
The pathological features of Alzheimer's disease (AD), a progressive neurodegenerative disorder, include the deposition of extracellular amyloid beta (Aβ) plaques and intracellular tau neurofibrillary tangles. A decline in cognitive ability is related to the accumulation of Aβ in patients with AD. Autophagy, which is a primary intracellular mechanism for degrading aggregated proteins and damaged organelles, plays a crucial role in AD. In this review, we summarize the most recent research progress regarding the process of autophagy and the effect of autophagy on Aβ. We further discuss some typical monomers of natural products that contribute to the clearance of Aβ by autophagy, which can alleviate AD. This provides a new perspective for the application of autophagy modulation in natural product therapy for AD.
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Affiliation(s)
- Min Hu
- Key Laboratory of Neuropsychiatric Drug Research of Zhejiang Province, Hangzhou Medical College, Hangzhou, Zhejiang 310013, PR China
| | - Xinyi Ying
- Key Laboratory of Neuropsychiatric Drug Research of Zhejiang Province, Hangzhou Medical College, Hangzhou, Zhejiang 310013, PR China
| | - Miao Zheng
- Key Laboratory of Neuropsychiatric Drug Research of Zhejiang Province, Hangzhou Medical College, Hangzhou, Zhejiang 310013, PR China
| | - Can Wang
- Key Laboratory of Neuropsychiatric Drug Research of Zhejiang Province, Hangzhou Medical College, Hangzhou, Zhejiang 310013, PR China
| | - Qin Li
- Key Laboratory of Neuropsychiatric Drug Research of Zhejiang Province, Hangzhou Medical College, Hangzhou, Zhejiang 310013, PR China
| | - Lili Gu
- Key Laboratory of Neuropsychiatric Drug Research of Zhejiang Province, Hangzhou Medical College, Hangzhou, Zhejiang 310013, PR China.
| | - Xinyue Zhang
- Key Laboratory of Neuropsychiatric Drug Research of Zhejiang Province, Hangzhou Medical College, Hangzhou, Zhejiang 310013, PR China.
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10
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Liu Y, Tan L, Tan MS. Chaperone-mediated autophagy in neurodegenerative diseases: mechanisms and therapy. Mol Cell Biochem 2023; 478:2173-2190. [PMID: 36695937 DOI: 10.1007/s11010-022-04640-9] [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: 07/18/2022] [Accepted: 12/09/2022] [Indexed: 01/26/2023]
Abstract
Chaperone-mediated autophagy (CMA) is the selective degradation process of intracellular components by lysosomes, which is required for the degradation of aggregate-prone proteins and contributes to proteostasis maintenance. Proteostasis is essential for normal cell function and survival, and it is determined by the balance of protein synthesis and degradation. Because postmitotic neurons are highly susceptible to proteostasis disruption, CMA is vital for the nervous system. Since Parkinson's disease (PD) was first linked to CMA dysfunction, an increasing number of studies have shown that CMA loss, as seen during aging, occurs in the pathogenetic process of neurodegenerative diseases. Here, we review the molecular mechanisms of CMA, as well as the physiological function and regulation of this autophagy pathway. Following, we highlight its potential role in neurodegenerative diseases, and the latest advances and challenges in targeting CMA in therapy of neurodegenerative diseases.
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Affiliation(s)
- Yi Liu
- Department of Neurology, Qingdao Municipal Hospital, Qingdao University, Qingdao, China
| | - Lan Tan
- Department of Neurology, Qingdao Municipal Hospital, Qingdao University, Qingdao, China.
| | - Meng-Shan Tan
- Department of Neurology, Qingdao Municipal Hospital, Qingdao University, Qingdao, China.
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11
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Yao R, Shen J. Chaperone-mediated autophagy: Molecular mechanisms, biological functions, and diseases. MedComm (Beijing) 2023; 4:e347. [PMID: 37655052 PMCID: PMC10466100 DOI: 10.1002/mco2.347] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Revised: 07/23/2023] [Accepted: 07/27/2023] [Indexed: 09/02/2023] Open
Abstract
Chaperone-mediated autophagy (CMA) is a lysosomal degradation pathway that eliminates substrate proteins through heat-shock cognate protein 70 recognition and lysosome-associated membrane protein type 2A-assisted translocation. It is distinct from macroautophagy and microautophagy. In recent years, the regulatory mechanisms of CMA have been gradually enriched, including the newly discovered NRF2 and p38-TFEB signaling, as positive and negative regulatory pathways of CMA, respectively. Normal CMA activity is involved in the regulation of metabolism, aging, immunity, cell cycle, and other physiological processes, while CMA dysfunction may be involved in the occurrence of neurodegenerative disorders, tumors, intestinal disorders, atherosclerosis, and so on, which provides potential targets for the treatment and prediction of related diseases. This article describes the general process of CMA and its role in physiological activities and summarizes the connection between CMA and macroautophagy. In addition, human diseases that concern the dysfunction or protective role of CMA are discussed. Our review deepens the understanding of the mechanisms and physiological functions of CMA and provides a summary of past CMA research and a vision of future directions.
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Affiliation(s)
- Ruchen Yao
- Division of Gastroenterology and HepatologyKey Laboratory of Gastroenterology and HepatologyMinistry of Health, Inflammatory Bowel Disease Research CenterShanghaiChina
- Renji Hospital, School of MedicineShanghai Jiao Tong UniversityShanghaiChina
- Shanghai Institute of Digestive DiseaseShanghaiChina
| | - Jun Shen
- Division of Gastroenterology and HepatologyKey Laboratory of Gastroenterology and HepatologyMinistry of Health, Inflammatory Bowel Disease Research CenterShanghaiChina
- Renji Hospital, School of MedicineShanghai Jiao Tong UniversityShanghaiChina
- Shanghai Institute of Digestive DiseaseShanghaiChina
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12
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Boťanská B, Pecníková V, Fogarassyová M, Barančík M. The Role of Heat Shock Proteins and Autophagy in Mechanisms Underlying Effects of Sulforaphane on Doxorubicin-Induced Toxicity in HEK293 Cells. Physiol Res 2023; 72:S47-S59. [PMID: 37294118 DOI: 10.33549/physiolres.935107] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/23/2023] Open
Abstract
Doxorubicin (DOX) is a cytostatic agent belonging to anthracycline group. Important role in mechanism associated with negative effects of DOX plays an oxidative stress. Heat shock proteins (HSPs) are part of mechanisms initiated in response to stressful stimuli and play an important role in cellular responses to oxidative stress through interaction with components of redox signaling. The present work was aimed to study the role of HSPs and autophagy in mechanisms underlying effects of sulforaphane (SFN), a potential activator of Nrf-2, on doxorubicin-induced toxicity in human kidney HEK293 cells. We investigated effects of SFN and DOX on proteins associated with regulation of heat shock response, redox signaling, and autophagy. Results show that SFN significantly reduced cytotoxic effects of DOX. The positive effects of SFN on DOX-induced changes were associated with up-regulation of Nrf-2 and HSP60 protein levels. In the case of another heat shock protein HSP40, SFN increased its levels when was administered alone but not in conditions when cells were exposed to the effects of DOX. Sulforaphane also reversed negative effects of DOX on activities of superoxide dismutases (SODs) and up-regulation of autophagy markers (LC3A/B-II, Atg5, and Atg12). In conclusion, the changes observed in HSP60 are of particular importance in terms of protecting cells from the effects of DOX. Finding that under conditions where SFN reduced cytotoxic effects of DOX were significantly increased protein levels of both Nrf-2 and HSP60 point to the role of HSP60 in mechanisms of redox signaling underlying effects of SFN on DOX-induced toxicity in HEK293 cells. Moreover, data confirmed an important role of autophagy in effects of SFN on DOX-induced toxicity.
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Affiliation(s)
- B Boťanská
- Centre of Experimental Medicine, Institute for Heart Research, Slovak Academy of Sciences, Bratislava, Slovak Republic.
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13
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Lazarev VF, Dutysheva EA, Kanunikov IE, Guzhova IV, Margulis BA. Protein Interactome of Amyloid-β as a Therapeutic Target. Pharmaceuticals (Basel) 2023; 16:312. [PMID: 37259455 PMCID: PMC9965366 DOI: 10.3390/ph16020312] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2022] [Revised: 01/27/2023] [Accepted: 02/08/2023] [Indexed: 04/12/2024] Open
Abstract
The amyloid concept of Alzheimer's disease (AD) assumes the β-amyloid peptide (Aβ) as the main pathogenic factor, which injures neural and other brain cells, causing their malfunction and death. Although Aβ has been documented to exert its cytotoxic effect in a solitary manner, there is much evidence to claim that its toxicity can be modulated by other proteins. The list of such Aβ co-factors or interactors includes tau, APOE, transthyretin, and others. These molecules interact with the peptide and affect the ability of Aβ to form oligomers or aggregates, modulating its toxicity. Thus, the list of potential substances able to reduce the harmful effects of the peptide should include ones that can prevent the pathogenic interactions by specifically binding Aβ and/or its partners. In the present review, we discuss the data on Aβ-based complexes in AD pathogenesis and on the compounds directly targeting Aβ or the destructors of its complexes with other polypeptides.
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Affiliation(s)
- Vladimir F. Lazarev
- Institute of Cytology of the Russian Academy of Sciences, 194064 Saint Petersburg, Russia
| | - Elizaveta A. Dutysheva
- Institute of Cytology of the Russian Academy of Sciences, 194064 Saint Petersburg, Russia
| | - Igor E. Kanunikov
- Biological Faculty, St. Petersburg State University, 199034 Saint Petersburg, Russia
| | - Irina V. Guzhova
- Institute of Cytology of the Russian Academy of Sciences, 194064 Saint Petersburg, Russia
| | - Boris A. Margulis
- Institute of Cytology of the Russian Academy of Sciences, 194064 Saint Petersburg, Russia
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14
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Ma X, Feng Y, Quan X, Geng B, Li G, Fu X, Zeng L. Multi-omics analysis revealed the role of CCT2 in the induction of autophagy in Alzheimer's disease. Front Genet 2023; 13:967730. [PMID: 36704351 PMCID: PMC9871314 DOI: 10.3389/fgene.2022.967730] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Accepted: 12/07/2022] [Indexed: 01/12/2023] Open
Abstract
Chaperonin containing TCP1 subunit 2 (CCT2) is essential in various neurodegenerative diseases, albeit its role in the pathogenesis of Alzheimer's disease (AD) remains elusive. This study aimed to evaluate the role of CCT2 in Alzheimer's disease. First, bioinformatics database analysis revealed that CCT2 was significantly downregulated in patients with Alzheimer's disease and associated with autophagic clearance of β-amyloid. The 789 differentially expressed genes overlapped in AD-group and CCT2-low/high group, and the CCT2-high-associated genes screened by Pearson coefficients were enriched in protein folding, autophagy, and messenger RNA stability regulation pathways. These results suggest that CCT2 is significantly and positively associated with multiple pathways linked to autophagy and negatively associated with neuronal death. The logistic prediction model with 13 key genes, such as CCT2, screened in this study better predicts Alzheimer's disease occurrence (AUC = 0.9671) and is a favorable candidate for predicting potential biological targets of Alzheimer's disease. Additionally, this study predicts reciprocal micro RNAs and small molecule drugs for hub genes. Our findings suggest that low CCT2 expression may be responsible for the autophagy suppression in Alzheimer's disease, providing an accurate explanation for its pathogenesis and new targets and small molecule inhibitors for its treatment.
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Affiliation(s)
- Xueting Ma
- Edmond H. Fischer Signal Transduction laboratory, School of Life Sciences, Jilin University, Changchun, China
| | - Yuxin Feng
- Edmond H. Fischer Signal Transduction laboratory, School of Life Sciences, Jilin University, Changchun, China
| | - Xiangyu Quan
- Edmond H. Fischer Signal Transduction laboratory, School of Life Sciences, Jilin University, Changchun, China
| | - Bingyu Geng
- Edmond H. Fischer Signal Transduction laboratory, School of Life Sciences, Jilin University, Changchun, China
| | - Guodong Li
- Department of General Surgery, The Second Hospital of Jilin University, Changchun, China
| | - Xueqi Fu
- Edmond H. Fischer Signal Transduction laboratory, School of Life Sciences, Jilin University, Changchun, China
| | - Linlin Zeng
- Edmond H. Fischer Signal Transduction laboratory, School of Life Sciences, Jilin University, Changchun, China,*Correspondence: Linlin Zeng,
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15
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He DL, Fan YG, Wang ZY. Energy Crisis Links to Autophagy and Ferroptosis in Alzheimer's Disease: Current Evidence and Future Avenues. Curr Neuropharmacol 2023; 21:67-86. [PMID: 35980072 PMCID: PMC10193753 DOI: 10.2174/1570159x20666220817140737] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Revised: 08/14/2022] [Accepted: 08/11/2022] [Indexed: 02/04/2023] Open
Abstract
Alzheimer's disease (AD) is one of the most common neurodegenerative diseases worldwide. The occult nature of the onset and the uncertainty of the etiology largely impede the development of therapeutic strategies for AD. Previous studies revealed that the disorder of energy metabolism in the brains of AD patients appears far earlier than the typical pathological features of AD, suggesting a tight association between energy crisis and the onset of AD. Energy crisis in the brain is known to be induced by the reductions in glucose uptake and utilization, which may be ascribed to the diminished expressions of cerebral glucose transporters (GLUTs), insulin resistance, mitochondrial dysfunctions, and lactate dysmetabolism. Notably, the energy sensors such as peroxisome proliferators-activated receptor (PPAR), transcription factor EB (TFEB), and AMP-activated protein kinase (AMPK) were shown to be the critical regulators of autophagy, which play important roles in regulating beta-amyloid (Aβ) metabolism, tau phosphorylation, neuroinflammation, iron dynamics, as well as ferroptosis. In this study, we summarized the current knowledge on the molecular mechanisms involved in the energy dysmetabolism of AD and discussed the interplays existing between energy crisis, autophagy, and ferroptosis. In addition, we highlighted the potential network in which autophagy may serve as a bridge between energy crisis and ferroptosis in the progression of AD. A deeper understanding of the relationship between energy dysmetabolism and AD may provide new insight into developing strategies for treating AD; meanwhile, the energy crisis in the progression of AD should gain more attention.
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Affiliation(s)
- Da-Long He
- Key Laboratory of Major Chronic Diseases of Nervous System of Liaoning Province, Health Sciences Institute of China Medical University, Shenyang, 110122, China
- Key Laboratory of Medical Cell Biology of Ministry of Education, Health Sciences Institute of China Medical University, Shenyang, 110122, China
| | - Yong-Gang Fan
- Key Laboratory of Major Chronic Diseases of Nervous System of Liaoning Province, Health Sciences Institute of China Medical University, Shenyang, 110122, China
- Key Laboratory of Medical Cell Biology of Ministry of Education, Health Sciences Institute of China Medical University, Shenyang, 110122, China
| | - Zhan-You Wang
- Key Laboratory of Major Chronic Diseases of Nervous System of Liaoning Province, Health Sciences Institute of China Medical University, Shenyang, 110122, China
- Key Laboratory of Medical Cell Biology of Ministry of Education, Health Sciences Institute of China Medical University, Shenyang, 110122, China
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16
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Gao Y, Wang C, Jiang D, An G, Jin F, Zhang J, Han G, Cui C, Jiang P. New insights into the interplay between autophagy and oxidative and endoplasmic reticulum stress in neuronal cell death and survival. Front Cell Dev Biol 2022; 10:994037. [PMID: 36187470 PMCID: PMC9524158 DOI: 10.3389/fcell.2022.994037] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Accepted: 08/30/2022] [Indexed: 12/03/2022] Open
Abstract
Autophagy is a dynamic process that maintains the normal homeostasis of cells by digesting and degrading aging proteins and damaged organelles. The effect of autophagy on neural tissue is still a matter of debate. Some authors suggest that autophagy has a protective effect on nerve cells, whereas others suggest that autophagy also induces the death of nerve cells and aggravates nerve injury. In mammals, oxidative stress, autophagy and endoplasmic reticulum stress (ERS) constitute important defense mechanisms to help cells adapt to and survive the stress conditions caused by physiological and pathological stimuli. Under many pathophysiological conditions, oxidative stress, autophagy and ERS are integrated and amplified in cells to promote the progress of diseases. Over the past few decades, oxidative stress, autophagy and ERS and their interactions have been a hot topic in biomedical research. In this review, we summarize recent advances in understanding the interactions between oxidative stress, autophagy and ERS in neuronal cell death and survival.
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Affiliation(s)
- Yahao Gao
- Clinical Medical School, Jining Medical University, Jining, China
| | - Changshui Wang
- Department of Neurosurgery, Affiliated Hospital of Jining Medical University, Jining, China
| | - Di Jiang
- Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Gang An
- Clinical Medical School, Jining Medical University, Jining, China
| | - Feng Jin
- Department of Neurosurgery, Affiliated Hospital of Jining Medical University, Jining, China
| | - Junchen Zhang
- Department of Neurosurgery, Affiliated Hospital of Jining Medical University, Jining, China
| | - Guangkui Han
- Department of Neurosurgery, Affiliated Hospital of Jining Medical University, Jining, China
| | - Changmeng Cui
- Department of Neurosurgery, Affiliated Hospital of Jining Medical University, Jining, China
- *Correspondence: Changmeng Cui, ; Pei Jiang,
| | - Pei Jiang
- Department of Clinical Pharmacy, Jining First People’s Hospital, Jining Medical University, Jining, China
- *Correspondence: Changmeng Cui, ; Pei Jiang,
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17
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Perez FP, Bandeira JP, Perez Chumbiauca CN, Lahiri DK, Morisaki J, Rizkalla M. Multidimensional insights into the repeated electromagnetic field stimulation and biosystems interaction in aging and age-related diseases. J Biomed Sci 2022; 29:39. [PMID: 35698225 PMCID: PMC9190166 DOI: 10.1186/s12929-022-00825-y] [Citation(s) in RCA: 7] [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: 12/20/2021] [Accepted: 06/07/2022] [Indexed: 11/25/2022] Open
Abstract
We provide a multidimensional sequence of events that describe the electromagnetic field (EMF) stimulation and biological system interaction. We describe this process from the quantum to the molecular, cellular, and organismal levels. We hypothesized that the sequence of events of these interactions starts with the oscillatory effect of the repeated electromagnetic stimulation (REMFS). These oscillations affect the interfacial water of an RNA causing changes at the quantum and molecular levels that release protons by quantum tunneling. Then protonation of RNA produces conformational changes that allow it to bind and activate Heat Shock Transcription Factor 1 (HSF1). Activated HSF1 binds to the DNA expressing chaperones that help regulate autophagy and degradation of abnormal proteins. This action helps to prevent and treat diseases such as Alzheimer's and Parkinson's disease (PD) by increasing clearance of pathologic proteins. This framework is based on multiple mathematical models, computer simulations, biophysical experiments, and cellular and animal studies. Results of the literature review and our research point towards the capacity of REMFS to manipulate various networks altered in aging (Reale et al. PloS one 9, e104973, 2014), including delay of cellular senescence (Perez et al. 2008, Exp Gerontol 43, 307-316) and reduction in levels of amyloid-β peptides (Aβ) (Perez et al. 2021, Sci Rep 11, 621). Results of these experiments using REMFS at low frequencies can be applied to the treatment of patients with age-related diseases. The use of EMF as a non-invasive therapeutic modality for Alzheimer's disease, specifically, holds promise. It is also necessary to consider the complicated and interconnected genetic and epigenetic effects of the REMFS-biological system's interaction while avoiding any possible adverse effects.
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Affiliation(s)
- Felipe P Perez
- Indiana University School of Medicine, Indianapolis, IN, USA.
- Division of General Internal Medicine and Geriatrics, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
| | - Joseph P Bandeira
- Indiana University School of Medicine, Indianapolis, IN, USA
- Division of General Internal Medicine and Geriatrics, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Cristina N Perez Chumbiauca
- Indiana University School of Medicine, Indianapolis, IN, USA
- Division of Rheumatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Debomoy K Lahiri
- Indiana University School of Medicine, Indianapolis, IN, USA
- Department of Psychiatry, Institute of Psychiatric Research, Neuroscience Research Center, Indiana University School of Medicine, Indianapolis, IN, USA
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Jorge Morisaki
- Department of Bioengineering, University of Illinois at Chicago, Chicago, IL, USA
| | - Maher Rizkalla
- Department of Electrical and Computer Engineering, Indiana University-Purdue University, Indianapolis, IN, USA
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18
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Zhang S, Liu T, Chen Q, Su M, Bai T, Zhang M, Hu Y, Li J, Chang F. Study on molecular mechanism of benzo (ɑ) pyrene on CMA by HSP90ɑ and HIF-1ɑ. Toxicol In Vitro 2022; 83:105372. [PMID: 35487446 DOI: 10.1016/j.tiv.2022.105372] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Revised: 04/19/2022] [Accepted: 04/22/2022] [Indexed: 11/16/2022]
Abstract
OBJECTIVE The effects of benzo (α) pyrene (BaP) on chaperone mediated autophagy (CMA) through heat shock protein 90 (HSP90) and hypoxia- inducible factor-1 (HIF-1) is studied by RNA interference and subcutaneous tumor formation technique in nude mice. METHODS 40 nude mice that were inoculated with the silenced HSP90ɑ A549 cell line under the armpits of the forelimbs were divided into 4 groups, and were intragastrically administered with 1.80 mg/kg/d BaP-corn oil solutionfor for 60d (except the Control group), and the growth curves of nude mice and transplanted tumors were recorded. The size and morphological changes of tumors were observed by small animal imaging technique. qPCR, Western blot and Immunohistochemistry were used to detect the expression of HSP90ɑ, HSC70 and Lamp-2A. A549 cells were treated with 0.1 μmol/L, 1 μmol/L and 10 μmol/L BaP for 24 h, EPO and HIF-1ɑ concentration and HIF-1ɑ protein expression were detected by Elisa and Western blot; A549 cells were treated with 10 μmol/L BaP and HIF-1ɑ inhibitor for 24 h, qPCR, Western blot and Immunofluorescence method were used to detect the expression of HSP90ɑ, HSC70 and Lamp-2A. RESULTS The weight of nude mice and transplanted tumors silenced HSP90ɑ was reduced by BaP (P < 0.01); the expression of HSP90ɑ, HSC70, Lamp-2A mRNA and protein in transplanted tumor tissues silenced HSP90ɑ was reduced by BaP (P < 0.05); the total number of bioluminescence photons of transplanted tumors silenced HSP90ɑ was reduced by BaP (P < 0.01). The concentration of EPO and HIF-1ɑ and the expression of HIF-1ɑ protein in A549 cells was increased by 10 μmol/L BaP (P < 0.05); with HIF-1ɑ inhibitors treated, HSP90ɑ, HSC70, Lamp-2A mRNA and protein expression and the fluorescence intensity of HSP90ɑ was decreased of A549 cells (P < 0.05). CONCLUSIONS The growth of transplanted tumor in nude mice is promoted by BaP, and is inhibited when HSP90ɑ was silenced. BaP promotes the occurrence of CMA by promoting the expression of HSP90ɑ and HIF-1ɑ, which is vital regulatory genes of BaP activation of CMA.
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Affiliation(s)
- Shasha Zhang
- School of Pharmacy, Inner Mongolia Medical University, PR China
| | - Tingting Liu
- School of Pharmacy, Inner Mongolia Medical University, PR China
| | - Qi Chen
- School of Pharmacy, Inner Mongolia Medical University, PR China
| | - Min Su
- School of Pharmacy, Inner Mongolia Medical University, PR China
| | - Tuya Bai
- School of Pharmacy, Inner Mongolia Medical University, PR China; New Drug Safety Evaluation Research Center, Inner Mongolia Medical University, Hohhot, Inner Mongolia Autonomous Region, PR China; New Drug Screening Engineering Research Center of Inner Mongolia Autonomous Region, Hohhot, Inner Mongolia Autonomous Region, PR China
| | - Mengdi Zhang
- School of Pharmacy, Inner Mongolia Medical University, PR China; New Drug Safety Evaluation Research Center, Inner Mongolia Medical University, Hohhot, Inner Mongolia Autonomous Region, PR China; New Drug Screening Engineering Research Center of Inner Mongolia Autonomous Region, Hohhot, Inner Mongolia Autonomous Region, PR China
| | - Yuxia Hu
- School of Pharmacy, Inner Mongolia Medical University, PR China; New Drug Safety Evaluation Research Center, Inner Mongolia Medical University, Hohhot, Inner Mongolia Autonomous Region, PR China; New Drug Screening Engineering Research Center of Inner Mongolia Autonomous Region, Hohhot, Inner Mongolia Autonomous Region, PR China
| | - Jun Li
- School of Pharmacy, Inner Mongolia Medical University, PR China; New Drug Safety Evaluation Research Center, Inner Mongolia Medical University, Hohhot, Inner Mongolia Autonomous Region, PR China; New Drug Screening Engineering Research Center of Inner Mongolia Autonomous Region, Hohhot, Inner Mongolia Autonomous Region, PR China
| | - Fuhou Chang
- School of Pharmacy, Inner Mongolia Medical University, PR China; New Drug Safety Evaluation Research Center, Inner Mongolia Medical University, Hohhot, Inner Mongolia Autonomous Region, PR China; New Drug Screening Engineering Research Center of Inner Mongolia Autonomous Region, Hohhot, Inner Mongolia Autonomous Region, PR China.
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19
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Chaperone-Mediated Autophagy in Neurodegenerative Diseases and Acute Neurological Insults in the Central Nervous System. Cells 2022; 11:cells11071205. [PMID: 35406769 PMCID: PMC8997510 DOI: 10.3390/cells11071205] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Revised: 03/27/2022] [Accepted: 03/30/2022] [Indexed: 12/12/2022] Open
Abstract
Autophagy is an important function that mediates the degradation of intracellular proteins and organelles. Chaperone-mediated autophagy (CMA) degrades selected proteins and has a crucial role in cellular proteostasis under various physiological and pathological conditions. CMA dysfunction leads to the accumulation of toxic protein aggregates in the central nervous system (CNS) and is involved in the pathogenic process of neurodegenerative diseases, including Parkinson’s disease and Alzheimer’s disease. Previous studies have suggested that the activation of CMA to degrade aberrant proteins can provide a neuroprotective effect in the CNS. Recent studies have shown that CMA activity is upregulated in damaged neural tissue following acute neurological insults, such as cerebral infarction, traumatic brain injury, and spinal cord injury. It has been also suggested that various protein degradation mechanisms are important for removing toxic aberrant proteins associated with secondary damage after acute neurological insults in the CNS. Therefore, enhancing the CMA pathway may induce neuroprotective effects not only in neurogenerative diseases but also in acute neurological insults. We herein review current knowledge concerning the biological mechanisms involved in CMA and highlight the role of CMA in neurodegenerative diseases and acute neurological insults. We also discuss the possibility of developing CMA-targeted therapeutic strategies for effective treatments.
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20
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The Interplay between Autophagy and Redox Signaling in Cardiovascular Diseases. Cells 2022; 11:cells11071203. [PMID: 35406767 PMCID: PMC8997791 DOI: 10.3390/cells11071203] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Revised: 03/29/2022] [Accepted: 03/31/2022] [Indexed: 12/20/2022] Open
Abstract
Reactive oxygen and nitrogen species produced at low levels under normal cellular metabolism act as important signal molecules. However, at increased production, they cause damage associated with oxidative stress, which can lead to the development of many diseases, such as cardiovascular, metabolic, neurodegenerative, diabetes, and cancer. The defense systems used to maintain normal redox homeostasis plays an important role in cellular responses to oxidative stress. The key players here are Nrf2-regulated redox signaling and autophagy. A tight interface has been described between these two processes under stress conditions and their role in oxidative stress-induced diseases progression. In this review, we focus on the role of Nrf2 as a key player in redox regulation in cell response to oxidative stress. We also summarize the current knowledge about the autophagy regulation and the role of redox signaling in this process. In line with the focus of our review, we describe in more detail information about the interplay between Nrf2 and autophagy pathways in myocardium and the role of these processes in cardiovascular disease development.
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21
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Fleming A, Bourdenx M, Fujimaki M, Karabiyik C, Krause GJ, Lopez A, Martín-Segura A, Puri C, Scrivo A, Skidmore J, Son SM, Stamatakou E, Wrobel L, Zhu Y, Cuervo AM, Rubinsztein DC. The different autophagy degradation pathways and neurodegeneration. Neuron 2022; 110:935-966. [PMID: 35134347 PMCID: PMC8930707 DOI: 10.1016/j.neuron.2022.01.017] [Citation(s) in RCA: 235] [Impact Index Per Article: 78.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2021] [Revised: 12/31/2021] [Accepted: 01/11/2022] [Indexed: 12/11/2022]
Abstract
The term autophagy encompasses different pathways that route cytoplasmic material to lysosomes for degradation and includes macroautophagy, chaperone-mediated autophagy, and microautophagy. Since these pathways are crucial for degradation of aggregate-prone proteins and dysfunctional organelles such as mitochondria, they help to maintain cellular homeostasis. As post-mitotic neurons cannot dilute unwanted protein and organelle accumulation by cell division, the nervous system is particularly dependent on autophagic pathways. This dependence may be a vulnerability as people age and these processes become less effective in the brain. Here, we will review how the different autophagic pathways may protect against neurodegeneration, giving examples of both polygenic and monogenic diseases. We have considered how autophagy may have roles in normal CNS functions and the relationships between these degradative pathways and different types of programmed cell death. Finally, we will provide an overview of recently described strategies for upregulating autophagic pathways for therapeutic purposes.
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Affiliation(s)
- Angeleen Fleming
- Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, The Keith Peters Building, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0XY, UK; UK Dementia Research Institute, University of Cambridge, Cambridge Institute for Medical Research, The Keith Peters Building, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0XY, UK; Department of Physiology, Development and Neuroscience, University of Cambridge, Downing Street, Cambridge CB2 3DY, UK
| | - Mathieu Bourdenx
- Université de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux, France; CNRS, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux, France
| | - Motoki Fujimaki
- Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, The Keith Peters Building, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0XY, UK; UK Dementia Research Institute, University of Cambridge, Cambridge Institute for Medical Research, The Keith Peters Building, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0XY, UK
| | - Cansu Karabiyik
- Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, The Keith Peters Building, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0XY, UK; UK Dementia Research Institute, University of Cambridge, Cambridge Institute for Medical Research, The Keith Peters Building, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0XY, UK
| | - Gregory J Krause
- Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY, USA; Institute for Aging Studies, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Ana Lopez
- Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, The Keith Peters Building, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0XY, UK; UK Dementia Research Institute, University of Cambridge, Cambridge Institute for Medical Research, The Keith Peters Building, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0XY, UK; Department of Physiology, Development and Neuroscience, University of Cambridge, Downing Street, Cambridge CB2 3DY, UK
| | - Adrián Martín-Segura
- Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY, USA; Institute for Aging Studies, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Claudia Puri
- Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, The Keith Peters Building, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0XY, UK; UK Dementia Research Institute, University of Cambridge, Cambridge Institute for Medical Research, The Keith Peters Building, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0XY, UK
| | - Aurora Scrivo
- Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY, USA; Institute for Aging Studies, Albert Einstein College of Medicine, Bronx, NY, USA
| | - John Skidmore
- The ALBORADA Drug Discovery Institute, University of Cambridge, Island Research Building, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0AH, UK
| | - Sung Min Son
- Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, The Keith Peters Building, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0XY, UK; UK Dementia Research Institute, University of Cambridge, Cambridge Institute for Medical Research, The Keith Peters Building, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0XY, UK
| | - Eleanna Stamatakou
- Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, The Keith Peters Building, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0XY, UK; UK Dementia Research Institute, University of Cambridge, Cambridge Institute for Medical Research, The Keith Peters Building, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0XY, UK
| | - Lidia Wrobel
- Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, The Keith Peters Building, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0XY, UK; UK Dementia Research Institute, University of Cambridge, Cambridge Institute for Medical Research, The Keith Peters Building, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0XY, UK
| | - Ye Zhu
- Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, The Keith Peters Building, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0XY, UK; UK Dementia Research Institute, University of Cambridge, Cambridge Institute for Medical Research, The Keith Peters Building, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0XY, UK
| | - Ana Maria Cuervo
- Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY, USA; Institute for Aging Studies, Albert Einstein College of Medicine, Bronx, NY, USA.
| | - David C Rubinsztein
- Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, The Keith Peters Building, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0XY, UK; UK Dementia Research Institute, University of Cambridge, Cambridge Institute for Medical Research, The Keith Peters Building, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0XY, UK.
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22
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Song H, Yang J, Yu W. Promoter Hypomethylation of TGFBR3 as a Risk Factor of Alzheimer’s Disease: An Integrated Epigenomic-Transcriptomic Analysis. Front Cell Dev Biol 2022; 9:825729. [PMID: 35310542 PMCID: PMC8924075 DOI: 10.3389/fcell.2021.825729] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Accepted: 12/29/2021] [Indexed: 11/13/2022] Open
Abstract
Alzheimer’s disease (AD) is characterized by the abnormal deposition of amyloid-β (Aβ) plaques and tau tangles in the brain and accompanied with cognitive impairment. However, the fundamental cause of this disease remains elusive. To elucidate the molecular processes related to AD, we carried out an integrated analysis utilizing gene expression microarrays (GSE36980 and GSE5281) and DNA methylation microarray (GSE66351) in temporal cortex of AD patients from the Gene Expression Omnibus (GEO) database. We totally discovered 409 aberrantly methylated and differentially expressed genes. These dysregulated genes were significantly enriched in biological processes including cell part morphogenesis, chemical synaptic transmission and regulation of Aβ formation. Through convergent functional genomic (CFG) analysis, expression cross-validation and clinicopathological correlation analysis, higher TGFBR3 level was observed in AD and positively correlated with Aβ accumulation. Meanwhile, the promoter methylation level of TGFBR3 was reduced in AD and negatively associated with Aβ level and advanced Braak stage. Mechanically, TGFBR3 might promote Aβ production by enhancing β- and γ-secretase activities. Further investigation revealed that TGFBR3 may exert its functions via Synaptic vesicle cycle, Calcium signaling pathway and MAPK signal pathway by regulating hub genes GNB1, GNG3, CDC5L, DYNC1H1 and FBXW7. Overall, our findings highlighted TGFBR3 as an AD risk gene and might be used as a diagnostic biomarker and therapeutic target for AD treatment.
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Affiliation(s)
- Hui Song
- Key Laboratory of Endemic and Ethnic Diseases, Ministry of Education and Key Laboratory of Medical Molecular Biology of Guizhou Province, School of Basic Medical Sciences, Guizhou Medical University, Guiyang, China
| | - Jue Yang
- The State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, China
- The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academic of Sciences, Guiyang, China
| | - Wenfeng Yu
- Key Laboratory of Endemic and Ethnic Diseases, Ministry of Education and Key Laboratory of Medical Molecular Biology of Guizhou Province, School of Basic Medical Sciences, Guizhou Medical University, Guiyang, China
- *Correspondence: Wenfeng Yu,
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23
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Watowich MM, Chiou KL, Montague MJ, Simons ND, Horvath JE, Ruiz-Lambides AV, Martínez MI, Higham JP, Brent LJN, Platt ML, Snyder-Mackler N. Natural disaster and immunological aging in a nonhuman primate. Proc Natl Acad Sci U S A 2022; 119:e2121663119. [PMID: 35131902 PMCID: PMC8872742 DOI: 10.1073/pnas.2121663119] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Accepted: 12/20/2021] [Indexed: 12/23/2022] Open
Abstract
Weather-related disasters are increasing in frequency and severity, leaving survivors to cope with ensuing mental, financial, and physical hardships. This adversity can exacerbate existing morbidities, trigger new ones, and increase the risk of mortality-features that are also characteristic of advanced age-inviting the hypothesis that extreme weather events may accelerate aging. To test this idea, we examined the impact of Hurricane Maria and its aftermath on immune cell gene expression in large, age-matched, cross-sectional samples from free-ranging rhesus macaques (Macaca mulatta) living on an isolated island. A cross section of macaques was sampled 1 to 4 y before (n = 435) and 1 y after (n = 108) the hurricane. Hurricane Maria was significantly associated with differential expression of 4% of immune-cell-expressed genes, and these effects were correlated with age-associated alterations in gene expression. We further found that individuals exposed to the hurricane had a gene expression profile that was, on average, 1.96 y older than individuals that were not-roughly equivalent to an increase in 7 to 8 y of a human life. Living through an intense hurricane and its aftermath was associated with expression of key immune genes, dysregulated proteostasis networks, and greater expression of inflammatory immune cell-specific marker genes. Together, our findings illuminate potential mechanisms through which the adversity unleashed by extreme weather and potentially other natural disasters might become biologically embedded, accelerate age-related molecular immune phenotypes, and ultimately contribute to earlier onset of disease and death.
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Affiliation(s)
- Marina M Watowich
- Department of Biology, University of Washington, Seattle, WA 98195
- Center for Evolution and Medicine, Arizona State University, Tempe, AZ 85281
- School of Life Sciences, Arizona State University, Tempe, AZ 85281
| | - Kenneth L Chiou
- Center for Evolution and Medicine, Arizona State University, Tempe, AZ 85281
- School of Life Sciences, Arizona State University, Tempe, AZ 85281
| | - Michael J Montague
- Department of Neuroscience, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104
| | - Noah D Simons
- Department of Evolutionary Anthropology, Duke University, Durham, NC 27708
| | - Julie E Horvath
- Department of Evolutionary Anthropology, Duke University, Durham, NC 27708
- Department of Biological and Biomedical Sciences, North Carolina Central University, Durham, NC 27707
- Research and Collections Section, North Carolina Museum of Natural Sciences, Raleigh, NC 27601
- Department of Biological Sciences, North Carolina State University, Raleigh, NC 27695
| | - Angelina V Ruiz-Lambides
- Caribbean Primate Research Center, Unit of Comparative Medicine, University of Puerto Rico, San Juan, PR 00936
| | - Melween I Martínez
- Caribbean Primate Research Center, Unit of Comparative Medicine, University of Puerto Rico, San Juan, PR 00936
| | - James P Higham
- Department of Anthropology, New York University, New York, NY 10003
- New York Consortium in Evolutionary Primatology, New York, NY 10016
| | - Lauren J N Brent
- Centre for Research in Animal Behaviour, University of Exeter, Exeter EX4 4QG, United Kingdom
| | - Michael L Platt
- Department of Neuroscience, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104
- Department of Psychology, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA 19104
- Marketing Department, Wharton School of Business, University of Pennsylvania, Philadelphia, PA 19104
| | - Noah Snyder-Mackler
- Department of Biology, University of Washington, Seattle, WA 98195;
- Center for Evolution and Medicine, Arizona State University, Tempe, AZ 85281
- School of Life Sciences, Arizona State University, Tempe, AZ 85281
- School of Human Evolution and Social Change, Arizona State University, Tempe, AZ 85281
- Department of Psychology, University of Washington, Seattle, WA 98195
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24
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Zhang Q, Wan XX, Hu XM, Zhao WJ, Ban XX, Huang YX, Yan WT, Xiong K. Targeting Programmed Cell Death to Improve Stem Cell Therapy: Implications for Treating Diabetes and Diabetes-Related Diseases. Front Cell Dev Biol 2021; 9:809656. [PMID: 34977045 PMCID: PMC8717932 DOI: 10.3389/fcell.2021.809656] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Accepted: 12/06/2021] [Indexed: 12/14/2022] Open
Abstract
Stem cell therapies have shown promising therapeutic effects in restoring damaged tissue and promoting functional repair in a wide range of human diseases. Generations of insulin-producing cells and pancreatic progenitors from stem cells are potential therapeutic methods for treating diabetes and diabetes-related diseases. However, accumulated evidence has demonstrated that multiple types of programmed cell death (PCD) existed in stem cells post-transplantation and compromise their therapeutic efficiency, including apoptosis, autophagy, necroptosis, pyroptosis, and ferroptosis. Understanding the molecular mechanisms in PCD during stem cell transplantation and targeting cell death signaling pathways are vital to successful stem cell therapies. In this review, we highlight the research advances in PCD mechanisms that guide the development of multiple strategies to prevent the loss of stem cells and discuss promising implications for improving stem cell therapy in diabetes and diabetes-related diseases.
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Affiliation(s)
- Qi Zhang
- Department of Anatomy and Neurobiology, School of Basic Medical Sciences, Central South University, Changsha, China
| | - Xin-xing Wan
- Department of Endocrinology, Third Xiangya Hospital, Central South University, Changsha, China
| | - Xi-min Hu
- Department of Anatomy and Neurobiology, School of Basic Medical Sciences, Central South University, Changsha, China
| | - Wen-juan Zhao
- Department of Anatomy and Neurobiology, School of Basic Medical Sciences, Central South University, Changsha, China
| | - Xiao-xia Ban
- Department of Anatomy and Neurobiology, School of Basic Medical Sciences, Central South University, Changsha, China
| | - Yan-xia Huang
- Department of Anatomy and Neurobiology, School of Basic Medical Sciences, Central South University, Changsha, China
| | - Wei-tao Yan
- Department of Anatomy and Neurobiology, School of Basic Medical Sciences, Central South University, Changsha, China
| | - Kun Xiong
- Department of Anatomy and Neurobiology, School of Basic Medical Sciences, Central South University, Changsha, China
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25
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The Emerging Roles of Autophagy in Human Diseases. Biomedicines 2021; 9:biomedicines9111651. [PMID: 34829881 PMCID: PMC8615641 DOI: 10.3390/biomedicines9111651] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Revised: 11/03/2021] [Accepted: 11/05/2021] [Indexed: 01/18/2023] Open
Abstract
Autophagy, a process of cellular self-digestion, delivers intracellular components including superfluous and dysfunctional proteins and organelles to the lysosome for degradation and recycling and is important to maintain cellular homeostasis. In recent decades, autophagy has been found to help fight against a variety of human diseases, but, at the same time, autophagy can also promote the procession of certain pathologies, which makes the connection between autophagy and diseases complex but interesting. In this review, we summarize the advances in understanding the roles of autophagy in human diseases and the therapeutic methods targeting autophagy and discuss some of the remaining questions in this field, focusing on cancer, neurodegenerative diseases, infectious diseases and metabolic disorders.
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26
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Cheng L, Wang Y, Xiang L, Qi J. Heat Shock Cognate 70 kDa Protein Is the Target of Tetradecyl 2,3-Dihydroxybenzoate for Neuritogenic Effect in PC12 Cells. Biomedicines 2021; 9:biomedicines9101483. [PMID: 34680600 PMCID: PMC8533567 DOI: 10.3390/biomedicines9101483] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Revised: 10/13/2021] [Accepted: 10/14/2021] [Indexed: 11/16/2022] Open
Abstract
Tetradecyl 2,3-dihydroxybenzoate (ABG-001) is a lead compound derived from gentisides with a remarkable neuritogenic activity. However, the target of ABG-001 is yet to be defined to date. In this study, the potential target of ABG-001 was investigated via an activity-based protein profiling (ABPP) analysis, which is a chemical proteomic method for target identification by using chemical probes. Results indicated that the potential target proteins of ABG-001 were heat shock cognate 70 kDa protein (Hsc70), 78 kDa glucose-regulated protein (GRP78), and 14-3-3 theta protein. Then, the potential target of ABG-001 was confirmed by using inhibitors, the cellular thermal shift assay (CETSA) and small-interfering RNA (siRNA) analysis. The inhibitor of Hsc70 and siRNA significantly decreased the neurite outgrowth induced by ABG-001. Furthermore, ABG-001 induced neurite outgrowth was reduced by siRNA against Hsc70, and the results of CETSA suggested that Hsc70 showed a significant thermal stability-shifted effect upon ABG-001 treatment. These results indicated that Hsc70 is the target protein of ABG-001 in PC12 cells.
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Affiliation(s)
| | | | - Lan Xiang
- Correspondence: (L.X.); (J.Q.); Tel./Fax: +86-571-8820-8627 (L.X. & J.Q.)
| | - Jianhua Qi
- Correspondence: (L.X.); (J.Q.); Tel./Fax: +86-571-8820-8627 (L.X. & J.Q.)
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27
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Silva NSM, Rodrigues LFDC, Dores-Silva PR, Montanari CA, Ramos CHI, Barbosa LRS, Borges JC. Structural, thermodynamic and functional studies of human 71 kDa heat shock cognate protein (HSPA8/hHsc70). BIOCHIMICA ET BIOPHYSICA ACTA-PROTEINS AND PROTEOMICS 2021; 1869:140719. [PMID: 34571256 DOI: 10.1016/j.bbapap.2021.140719] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/01/2021] [Revised: 08/29/2021] [Accepted: 09/21/2021] [Indexed: 01/14/2023]
Abstract
Human 71 kDa heat shock cognate protein (HSPA8, also known as Hsc70, Hsp70-8, Hsc71, Hsp71 or Hsp73) is a constitutively expressed chaperone that is critical for cell proteostasis. In the cytosol, HSPA8 plays a pivotal role in folding and refolding, facilitates protein trafficking across membranes and targets proteins for degradation, among other functions. Here, we report an in solution study of recombinant HSPA8 (rHSPA8) using a variety of biophysical and biochemical approaches. rHSPA8 shares several structural and functional similarities with others human Hsp70s. It has two domains with different stabilities and interacts with adenosine nucleotides with dissociation constants in the low micromolar range, which were higher in the presence of Mg2+. rHSPA8 showed lower ATPase activity than its homolog HSPA5/hGrp78/hBiP, but it was 4-fold greater than that of recombinant HSPA1A/hHsp70-1A, with which it is 86% identical. Small angle X-ray scattering indicated that rHSPA8 behaved as an elongated monomeric protein in solution with dimensions similar to those observed for HSPA1A. In addition, rHSPA8 showed structural flexibility between its compacted and extended conformations. The data also indicated that HSPA8 has capacity in preventing the aggregation of model client proteins. The present study expands the understanding of the structure and activity of this chaperone and aligns with the idea that human homologous Hsp70s have divergent functions.
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Affiliation(s)
| | | | - Paulo Roberto Dores-Silva
- São Carlos Institute of Chemistry, University of São Paulo, São Carlos, SP, Brazil; Division of Trauma, Critical Care, Burns and Acute Care Surgery, Department of Surgery School of Medicine, University of California San Diego, La Jolla, CA 92093, USA
| | | | | | - Leandro Ramos Souza Barbosa
- Institute of Physics, University of São Paulo, São Paulo, SP, Brazil; Brazilian Synchrotron Light Laboratory (LNLS), Brazilian Center for Research in Energy and Materials (CNPEM), Campinas, Brazil
| | - Júlio César Borges
- São Carlos Institute of Chemistry, University of São Paulo, São Carlos, SP, Brazil.
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28
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Peptides for disrupting and degrading amyloids. Curr Opin Chem Biol 2021; 64:124-130. [PMID: 34274561 DOI: 10.1016/j.cbpa.2021.05.011] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2021] [Revised: 05/13/2021] [Accepted: 05/18/2021] [Indexed: 01/23/2023]
Abstract
Amyloid proteins can aggregate into insoluble fibrils and form amyloid deposits in the human brain, which is the hallmark of many neurodegenerative diseases. Promising strategies toward pathological amyloid proteins and deposition include investigating inhibitors that can disrupt amyloid aggregation or induce misfolding protein degradation. In this review, recent progress of peptide-based inhibitors, including amyloid sequence-derived inhibitors, designed peptides, and peptide mimics, is highlighted. Based on the increased understanding of peptide design and precise amyloid structures, these peptides exhibit advanced inhibitory activities against fibrous aggregation as well as enhanced druggability.
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29
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Hu XM, Zhang Q, Zhou RX, Wu YL, Li ZX, Zhang DY, Yang YC, Yang RH, Hu YJ, Xiong K. Programmed cell death in stem cell-based therapy: Mechanisms and clinical applications. World J Stem Cells 2021; 13:386-415. [PMID: 34136072 PMCID: PMC8176847 DOI: 10.4252/wjsc.v13.i5.386] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 04/26/2021] [Accepted: 05/07/2021] [Indexed: 02/06/2023] Open
Abstract
Stem cell-based therapy raises hopes for a better approach to promoting tissue repair and functional recovery. However, transplanted stem cells show a high death percentage, creating challenges to successful transplantation and prognosis. Thus, it is necessary to investigate the mechanisms underlying stem cell death, such as apoptotic cascade activation, excessive autophagy, inflammatory response, reactive oxygen species, excitotoxicity, and ischemia/hypoxia. Targeting the molecular pathways involved may be an efficient strategy to enhance stem cell viability and maximize transplantation success. Notably, a more complex network of cell death receives more attention than one crucial pathway in determining stem cell fate, highlighting the challenges in exploring mechanisms and therapeutic targets. In this review, we focus on programmed cell death in transplanted stem cells. We also discuss some promising strategies and challenges in promoting survival for further study.
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Affiliation(s)
- Xi-Min Hu
- Department of Anatomy and Neurobiology, School of Basic Medical Sciences, Central South University, Changsha 410013, Hunan Province, China
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha 410013, Hunan Province, China
| | - Qi Zhang
- Department of Anatomy and Neurobiology, School of Basic Medical Sciences, Central South University, Changsha 410013, Hunan Province, China
| | - Rui-Xin Zhou
- Department of Anatomy and Neurobiology, School of Basic Medical Sciences, Central South University, Changsha 410013, Hunan Province, China
| | - Yan-Lin Wu
- Department of Anatomy and Neurobiology, School of Basic Medical Sciences, Central South University, Changsha 410013, Hunan Province, China
| | - Zhi-Xin Li
- Department of Anatomy and Neurobiology, School of Basic Medical Sciences, Central South University, Changsha 410013, Hunan Province, China
| | - Dan-Yi Zhang
- Department of Anatomy and Neurobiology, School of Basic Medical Sciences, Central South University, Changsha 410013, Hunan Province, China
| | - Yi-Chao Yang
- Department of Anatomy and Neurobiology, School of Basic Medical Sciences, Central South University, Changsha 410013, Hunan Province, China
| | - Rong-Hua Yang
- Department of Burns, Fo Shan Hospital of Sun Yat-Sen University, Foshan 528000, Guangdong Province, China
| | - Yong-Jun Hu
- Department of Cardiovascular Medicine, Hunan People's Hospital (the First Affiliated Hospital of Hunan Normal University, Changsha 410005, Hunan Province, China
| | - Kun Xiong
- Department of Anatomy and Neurobiology, School of Basic Medical Sciences, Central South University, Changsha 410013, Hunan Province, China
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30
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Auzmendi-Iriarte J, Matheu A. Impact of Chaperone-Mediated Autophagy in Brain Aging: Neurodegenerative Diseases and Glioblastoma. Front Aging Neurosci 2021; 12:630743. [PMID: 33633561 PMCID: PMC7901968 DOI: 10.3389/fnagi.2020.630743] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Accepted: 12/21/2020] [Indexed: 12/11/2022] Open
Abstract
Brain aging is characterized by a time-dependent decline of tissue integrity and function, and it is a major risk for neurodegenerative diseases and brain cancer. Chaperone-mediated autophagy (CMA) is a selective form of autophagy specialized in protein degradation, which is based on the individual translocation of a cargo protein through the lysosomal membrane. Regulation of processes such as proteostasis, cellular energetics, or immune system activity has been associated with CMA, indicating its pivotal role in tissue homeostasis. Since first studies associating Parkinson’s disease (PD) to CMA dysfunction, increasing evidence points out that CMA is altered in both physiological and pathological brain aging. In this review article, we summarize the current knowledge regarding the impact of CMA during aging in brain physiopathology, highlighting the role of CMA in neurodegenerative diseases and glioblastoma, the most common and aggressive brain tumor in adults.
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Affiliation(s)
| | - Ander Matheu
- Cellular Oncology Group, Biodonostia Health Research Institute, San Sebastian, Spain.,CIBER de Fragilidad y Envejecimiento Saludable (CIBERfes), Madrid, Spain.,IKERBASQUE, Basque Foundation, Bilbao, Spain
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31
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Autophagy status as a gateway for stress-induced catecholamine interplay in neurodegeneration. Neurosci Biobehav Rev 2021; 123:238-256. [PMID: 33497785 DOI: 10.1016/j.neubiorev.2021.01.015] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2020] [Revised: 01/08/2021] [Accepted: 01/09/2021] [Indexed: 12/13/2022]
Abstract
The catecholamine-containing brainstem nuclei locus coeruleus (LC) and ventral tegmental area (VTA) are critically involved in stress responses. Alterations of catecholamine systems during chronic stress may contribute to neurodegeneration, including cognitive decline. Stress-related catecholamine alterations, while contributing to anxiety and depression, might accelerate neuronal degeneration by increasing the formation of toxic dopamine and norepinephrine by-products. These, in turn, may impair proteostasis within a variety of cortical and subcortical areas. In particular, the molecular events governing neurotransmission, neuroplasticity, and proteostasis within LC and VTA affect a variety of brain areas. Therefore, we focus on alterations of autophagy machinery in these nuclei as a relevant trigger in this chain of events. In fact, these catecholamine-containing areas are mostly prone to autophagy-dependent neurodegeneration. Thus, we propose a dynamic hypothesis according to which stress-induced autophagy alterations within the LC-VTA network foster a cascade towards early neurodegeneration within these nuclei.
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32
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Zhang W, Feng C, Jiang H. Novel target for treating Alzheimer's Diseases: Crosstalk between the Nrf2 pathway and autophagy. Ageing Res Rev 2021; 65:101207. [PMID: 33144123 DOI: 10.1016/j.arr.2020.101207] [Citation(s) in RCA: 97] [Impact Index Per Article: 24.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2020] [Revised: 10/02/2020] [Accepted: 10/27/2020] [Indexed: 02/06/2023]
Abstract
In mammals, the Keap1-Nrf2-ARE pathway (henceforth, "the Nrf2 pathway") and autophagy are major intracellular defence systems that combat oxidative damage and maintain homeostasis. p62/SQSTM1, a ubiquitin-binding autophagy receptor protein, links the Nrf2 pathway and autophagy. Phosphorylation of p62 dramatically enhances its affinity for Keap1, which induces Keap1 to release Nrf2, and the p62-Keap1 heterodimer recruits LC3 and mediates the permanent degradation of Keap1 in the selective autophagy pathway. Eventually, Nrf2 accumulates in the cytoplasm and then translocates into the nucleus to activate the transcription of downstream genes that encode antioxidant enzymes, which protect cells from oxidative damage. Since Nrf2 also upregulates the expression of the p62 gene, a p62-Keap1-Nrf2 positive feedback loop is created that further enhances the protective effect on cells. Studies have shown that the p62-activated noncanonical Nrf2 pathway is an important marker of neurodegenerative diseases. The p62-Keap1-Nrf2 positive feedback loop and the Nrf2 pathway are involved in eliminating the ROS and protein aggregates induced by AD. Therefore, maintaining the homeostasis of the p62-Keap1-Nrf2 positive feedback loop, which is a bridge between the Nrf2 pathway and autophagy, may be a potential target for the treatment of AD.
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Affiliation(s)
- Weiwei Zhang
- Department of Health Laboratory Technology, School of Public Health, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning 110122, People's Republic of China
| | - Cong Feng
- Department of Health Laboratory Technology, School of Public Health, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning 110122, People's Republic of China
| | - Hong Jiang
- Department of Health Laboratory Technology, School of Public Health, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning 110122, People's Republic of China.
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