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Yu P, Liu B, Dong C, Chang Y. Induced Pluripotent Stem Cells-Based Regenerative Therapies in Treating Human Aging-Related Functional Decline and Diseases. Cells 2025; 14:619. [PMID: 40277944 PMCID: PMC12025799 DOI: 10.3390/cells14080619] [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: 03/11/2025] [Revised: 04/15/2025] [Accepted: 04/17/2025] [Indexed: 04/26/2025] Open
Abstract
A significant increase in life expectancy worldwide has resulted in a growing aging population, accompanied by a rise in aging-related diseases that pose substantial societal, economic, and medical challenges. This trend has prompted extensive efforts within many scientific and medical communities to develop and enhance therapies aimed at delaying aging processes, mitigating aging-related functional decline, and addressing aging-associated diseases to extend health span. Research in aging biology has focused on unraveling various biochemical and genetic pathways contributing to aging-related changes, including genomic instability, telomere shortening, and cellular senescence. The advent of induced pluripotent stem cells (iPSCs), derived through reprogramming human somatic cells, has revolutionized disease modeling and understanding in humans by addressing the limitations of conventional animal models and primary human cells. iPSCs offer significant advantages over other pluripotent stem cells, such as embryonic stem cells, as they can be obtained without the need for embryo destruction and are not restricted by the availability of healthy donors or patients. These attributes position iPSC technology as a promising avenue for modeling and deciphering mechanisms that underlie aging and associated diseases, as well as for studying drug effects. Moreover, iPSCs exhibit remarkable versatility in differentiating into diverse cell types, making them a promising tool for personalized regenerative therapies aimed at replacing aged or damaged cells with healthy, functional equivalents. This review explores the breadth of research in iPSC-based regenerative therapies and their potential applications in addressing a spectrum of aging-related conditions.
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Affiliation(s)
- Peijie Yu
- Department of Biomedical Engineering, The Hong Kong Polytechnic University, Hunghom, Hong Kong 999077, China; (P.Y.); (B.L.)
- The Hong Kong Polytechnic University Shenzhen Research Institute, Shenzhen 518057, China
| | - Bin Liu
- Department of Biomedical Engineering, The Hong Kong Polytechnic University, Hunghom, Hong Kong 999077, China; (P.Y.); (B.L.)
- The Hong Kong Polytechnic University Shenzhen Research Institute, Shenzhen 518057, China
| | - Cheng Dong
- Department of Biomedical Engineering, The Hong Kong Polytechnic University, Hunghom, Hong Kong 999077, China; (P.Y.); (B.L.)
- The Hong Kong Polytechnic University Shenzhen Research Institute, Shenzhen 518057, China
| | - Yun Chang
- Department of Biomedical Engineering, The Hong Kong Polytechnic University, Hunghom, Hong Kong 999077, China; (P.Y.); (B.L.)
- The Hong Kong Polytechnic University Shenzhen Research Institute, Shenzhen 518057, China
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Ms S, Banerjee S, D'Mello SR, Dastidar SG. Amyotrophic Lateral Sclerosis: Focus on Cytoplasmic Trafficking and Proteostasis. Mol Neurobiol 2025:10.1007/s12035-025-04831-7. [PMID: 40180687 DOI: 10.1007/s12035-025-04831-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2024] [Accepted: 03/09/2025] [Indexed: 04/05/2025]
Abstract
Amyotrophic lateral sclerosis (ALS) is a progressive and fatal motor neuron disease characterized by the pathological loss of upper and lower motor neurons. Whereas most ALS cases are caused by a combination of environmental factors and genetic susceptibility, in a relatively small proportion of cases, the disorder results from mutations in genes that are inherited. Defects in several different cellular mechanisms and processes contribute to the selective loss of motor neurons (MNs) in ALS. Prominent among these is the accumulation of aggregates of misfolded proteins or peptides which are toxic to motor neurons. These accumulating aggregates stress the ability of the endoplasmic reticulum (ER) to function normally, cause defects in the transport of proteins between the ER and Golgi, and impair the transport of RNA, proteins, and organelles, such as mitochondria, within axons and dendrites, all of which contribute to the degeneration of MNs. Although dysfunction of a variety of cellular processes combines towards the pathogenesis of ALS, in this review, we focus on recent advances concerning the involvement of defective ER stress, vesicular transport between the ER and Golgi, and axonal transport.
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Affiliation(s)
- Shrilaxmi Ms
- Center for Molecular Neuroscience, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India
| | - Saradindu Banerjee
- Center for Molecular Neuroscience, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India
| | - Santosh R D'Mello
- Center for Molecular Neuroscience, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India.
- College of Arts and Sciences, Louisiana State University, Shreveport, LA, 71115, USA.
| | - Somasish Ghosh Dastidar
- Center for Molecular Neuroscience, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India.
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Baker ZN, Zhu Y, Guerra RM, Smith AJ, Arra A, Serrano LR, Overmyer KA, Mukherji S, Craig EA, Coon JJ, Pagliarini DJ. Triacylglycerol mobilization underpins mitochondrial stress recovery. Nat Cell Biol 2025; 27:298-308. [PMID: 39779944 PMCID: PMC11821527 DOI: 10.1038/s41556-024-01586-6] [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: 06/04/2024] [Accepted: 11/26/2024] [Indexed: 01/11/2025]
Abstract
Mitochondria are central to myriad biochemical processes, and thus even their moderate impairment could have drastic cellular consequences if not rectified. Here, to explore cellular strategies for surmounting mitochondrial stress, we conducted a series of chemical and genetic perturbations to Saccharomyces cerevisiae and analysed the cellular responses using deep multiomic mass spectrometry profiling. We discovered that mobilization of lipid droplet triacylglycerol stores was necessary for strains to mount a successful recovery response. In particular, acyl chains from these stores were liberated by triacylglycerol lipases and used to fuel biosynthesis of the quintessential mitochondrial membrane lipid cardiolipin to support new mitochondrial biogenesis. We demonstrate that a comparable recovery pathway exists in mammalian cells, which fail to recover from doxycycline treatment when lacking the ATGL lipase. Collectively, our work reveals a key component of mitochondrial stress recovery and offers a rich resource for further exploration of the broad cellular responses to mitochondrial dysfunction.
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Affiliation(s)
- Zakery N Baker
- Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO, USA
| | - Yunyun Zhu
- Department of Chemistry, University of Wisconsin-Madison, Madison, WI, USA
- National Center for Quantitative Biology of Complex Systems, Madison, WI, USA
| | - Rachel M Guerra
- Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO, USA
| | - Andrew J Smith
- Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO, USA
| | - Aline Arra
- Department of Physics, Washington University, St. Louis, MO, USA
| | - Lia R Serrano
- Department of Chemistry, University of Wisconsin-Madison, Madison, WI, USA
- National Center for Quantitative Biology of Complex Systems, Madison, WI, USA
| | - Katherine A Overmyer
- Department of Chemistry, University of Wisconsin-Madison, Madison, WI, USA
- National Center for Quantitative Biology of Complex Systems, Madison, WI, USA
- Morgridge Institute for Research, Madison, WI, USA
| | - Shankar Mukherji
- Department of Physics, Washington University, St. Louis, MO, USA
| | - Elizabeth A Craig
- Department of Biochemistry, University of Wisconsin-Madison, Madison, WI, USA
| | - Joshua J Coon
- Department of Chemistry, University of Wisconsin-Madison, Madison, WI, USA
- National Center for Quantitative Biology of Complex Systems, Madison, WI, USA
- Morgridge Institute for Research, Madison, WI, USA
- Department of Biomolecular Chemistry, University of Wisconsin-Madison, Madison, WI, USA
| | - David J Pagliarini
- Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO, USA.
- Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO, USA.
- Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA.
- Howard Hughes Medical Institute, Washington University School of Medicine, St. Louis, MO, USA.
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Toader C, Tataru CP, Munteanu O, Serban M, Covache-Busuioc RA, Ciurea AV, Enyedi M. Decoding Neurodegeneration: A Review of Molecular Mechanisms and Therapeutic Advances in Alzheimer's, Parkinson's, and ALS. Int J Mol Sci 2024; 25:12613. [PMID: 39684324 PMCID: PMC11641752 DOI: 10.3390/ijms252312613] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2024] [Revised: 11/21/2024] [Accepted: 11/22/2024] [Indexed: 12/18/2024] Open
Abstract
Neurodegenerative diseases, such as Alzheimer's, Parkinson's, ALS, and Huntington's, remain formidable challenges in medicine, with their relentless progression and limited therapeutic options. These diseases arise from a web of molecular disturbances-misfolded proteins, chronic neuroinflammation, mitochondrial dysfunction, and genetic mutations-that slowly dismantle neuronal integrity. Yet, recent scientific breakthroughs are opening new paths to intervene in these once-intractable conditions. This review synthesizes the latest insights into the underlying molecular dynamics of neurodegeneration, revealing how intertwined pathways drive the course of these diseases. With an eye on the most promising advances, we explore innovative therapies emerging from cutting-edge research: nanotechnology-based drug delivery systems capable of navigating the blood-brain barrier, gene-editing tools like CRISPR designed to correct harmful genetic variants, and stem cell strategies that not only replace lost neurons but foster neuroprotective environments. Pharmacogenomics is reshaping treatment personalization, enabling tailored therapies that align with individual genetic profiles, while molecular diagnostics and biomarkers are ushering in an era of early, precise disease detection. Furthermore, novel perspectives on the gut-brain axis are sparking interest as mounting evidence suggests that microbiome modulation may play a role in reducing neuroinflammatory responses linked to neurodegenerative progression. Taken together, these advances signal a shift toward a comprehensive, personalized approach that could transform neurodegenerative care. By integrating molecular insights and innovative therapeutic techniques, this review offers a forward-looking perspective on a future where treatments aim not just to manage symptoms but to fundamentally alter disease progression, presenting renewed hope for improved patient outcomes.
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Affiliation(s)
- Corneliu Toader
- Department of Neurosurgery, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania; (C.T.); (M.S.); (R.-A.C.-B.); (A.V.C.)
- Department of Vascular Neurosurgery, National Institute of Neurology and Neurovascular Diseases, 077160 Bucharest, Romania
| | - Calin Petru Tataru
- Ophthalmology Department, “Carol Davila” University of Medicine and Pharmacy, 020021 Bucharest, Romania
| | - Octavian Munteanu
- Department of Anatomy, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania;
| | - Matei Serban
- Department of Neurosurgery, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania; (C.T.); (M.S.); (R.-A.C.-B.); (A.V.C.)
| | - Razvan-Adrian Covache-Busuioc
- Department of Neurosurgery, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania; (C.T.); (M.S.); (R.-A.C.-B.); (A.V.C.)
- Department of Vascular Neurosurgery, National Institute of Neurology and Neurovascular Diseases, 077160 Bucharest, Romania
| | - Alexandru Vlad Ciurea
- Department of Neurosurgery, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania; (C.T.); (M.S.); (R.-A.C.-B.); (A.V.C.)
- Neurosurgery Department, Sanador Clinical Hospital, 010991 Bucharest, Romania
- Medical Section within the Romanian Academy, 010071 Bucharest, Romania
| | - Mihaly Enyedi
- Department of Anatomy, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania;
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Torres-Rico M, García-Calvo V, Gironda-Martínez A, Pascual-Guerra J, García AG, Maneu V. Targeting calciumopathy for neuroprotection: focus on calcium channels Cav1, Orai1 and P2X7. Cell Calcium 2024; 123:102928. [PMID: 39003871 DOI: 10.1016/j.ceca.2024.102928] [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: 05/30/2024] [Revised: 07/02/2024] [Accepted: 07/05/2024] [Indexed: 07/16/2024]
Abstract
As the uncontrolled entry of calcium ions (Ca2+) through plasmalemmal calcium channels is a cell death trigger, the conjecture is here raised that mitigating such an excess of Ca2+ entry should rescue from death the vulnerable neurons in neurodegenerative diseases (NDDs). However, this supposition has failed in some clinical trials (CTs). Thus, a recent CT tested whether isradipine, a blocker of the Cav1 subtype of voltage-operated calcium channels (VOCCs), exerted a benefit in patients with Parkinson's disease (PD); however, outcomes were negative. This is one more of the hundreds of CTs done under the principle of one-drug-one-target, that have failed in Alzheimer's disease (AD) and other NDDs during the last three decades. As there are myriad calcium channels to let Ca2+ ions gain the cell cytosol, it seems reasonable to predict that blockade of Ca2+ entry through a single channel may not be capable of preventing the Ca2+ flood of cells by the uncontrolled Ca2+ entry. Furthermore, as Ca2+ signaling is involved in the regulation of myriad functions in different cell types, it seems also reasonable to guess that a therapy should be more efficient by targeting different cells with various drugs. Here, we propose to mitigate Ca2+ entry by the simultaneous partial blockade of three quite different subtypes of plasmalemmal calcium channels that is, the Cav1 subtype of VOCCs, the Orai1 store-operated calcium channel (SOCC), and the purinergic P2X7 calcium channel. All three channels are expressed in both microglia and neurons. Thus, by targeting the three channels with a combination of three drug blockers we expect favorable changes in some of the pathogenic features of NDDs, namely (i) to mitigate Ca2+ entry into microglia; (ii) to decrease the Ca2+-dependent microglia activation; (iii) to decrease the sustained neuroinflammation; (iv) to decrease the uncontrolled Ca2+ entry into neurons; (v) to rescue vulnerable neurons from death; and (vi) to delay disease progression. In this review we discuss the arguments underlying our triad hypothesis in the sense that the combination of three repositioned medicines targeting Cav1, Orai1, and P2X7 calcium channels could boost neuroprotection and delay the progression of AD and other NDDs.
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Affiliation(s)
| | | | - Adrián Gironda-Martínez
- Instituto Fundación Teófilo Hernando, Madrid, Spain; Departamento de Farmacología y Terapéutica, Universidad Autónoma de Madrid, Madrid, Spain
| | | | - Antonio G García
- Instituto Fundación Teófilo Hernando, Madrid, Spain; Departamento de Farmacología y Terapéutica, Universidad Autónoma de Madrid, Madrid, Spain; Facultad de Medicina, Instituto de Investigación Sanitaria del Hospital Universitario La Princesa, Universidad Autónoma de Madrid, Madrid, Spain.
| | - Victoria Maneu
- Departamento de Óptica, Farmacología y Anatomía, Universidad de Alicante, Alicante, Spain.
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Quach TT, Stratton HJ, Khanna R, Mackey-Alfonso S, Deems N, Honnorat J, Meyer K, Duchemin AM. Neurodegenerative Diseases: From Dysproteostasis, Altered Calcium Signalosome to Selective Neuronal Vulnerability to AAV-Mediated Gene Therapy. Int J Mol Sci 2022; 23:ijms232214188. [PMID: 36430666 PMCID: PMC9694178 DOI: 10.3390/ijms232214188] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Revised: 11/01/2022] [Accepted: 11/04/2022] [Indexed: 11/18/2022] Open
Abstract
Despite intense research into the multifaceted etiology of neurodegenerative diseases (ND), they remain incurable. Here we provide a brief overview of several major ND and explore novel therapeutic approaches. Although the cause (s) of ND are not fully understood, the accumulation of misfolded/aggregated proteins in the brain is a common pathological feature. This aggregation may initiate disruption of Ca++ signaling, which is an early pathological event leading to altered dendritic structure, neuronal dysfunction, and cell death. Presently, ND gene therapies remain unidimensional, elusive, and limited to modifying one pathological feature while ignoring others. Considering the complexity of signaling cascades in ND, we discuss emerging therapeutic concepts and suggest that deciphering the molecular mechanisms involved in dendritic pathology may broaden the phenotypic spectrum of ND treatment. An innovative multiplexed gene transfer strategy that employs silencing and/or over-expressing multiple effectors could preserve vulnerable neurons before they are lost. Such therapeutic approaches may extend brain health span and ameliorate burdensome chronic disease states.
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Affiliation(s)
- Tam T. Quach
- Institute for Behavioral Medicine Research, Wexner Medical Center, The Ohio State University, Columbus, OH 43210, USA
- INSERM U1217/CNRS UMR5310, Université de Lyon, Université Claude Bernard Lyon 1, 69677 Lyon, France
| | | | - Rajesh Khanna
- Department of Molecular Pathobiology, New York University, New York, NY 10010, USA
| | - Sabrina Mackey-Alfonso
- Institute for Behavioral Medicine Research, Wexner Medical Center, The Ohio State University, Columbus, OH 43210, USA
| | - Nicolas Deems
- Institute for Behavioral Medicine Research, Wexner Medical Center, The Ohio State University, Columbus, OH 43210, USA
| | - Jérome Honnorat
- INSERM U1217/CNRS UMR5310, Université de Lyon, Université Claude Bernard Lyon 1, 69677 Lyon, France
- French Reference Center on Paraneoplastic Neurological Syndromes and Autoimmune Encephalitis, Hospices Civils de Lyon, 69677 Lyon, France
- SynatAc Team, Institut NeuroMyoGène, 69677 Lyon, France
| | - Kathrin Meyer
- The Research Institute of Nationwide Children Hospital, Columbus, OH 43205, USA
- Department of Pediatric, The Ohio State University, Columbus, OH 43210, USA
| | - Anne-Marie Duchemin
- Department of Psychiatry and Behavioral Health, The Ohio State University, Columbus, OH 43210, USA
- Correspondence: ; Tel.: +1-614-293-5517; Fax: +1-614-293-7599
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7
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PolyGA targets the ER stress-adaptive response by impairing GRP75 function at the MAM in C9ORF72-ALS/FTD. Acta Neuropathol 2022; 144:939-966. [PMID: 36121477 PMCID: PMC9547809 DOI: 10.1007/s00401-022-02494-5] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2022] [Revised: 08/18/2022] [Accepted: 09/06/2022] [Indexed: 01/26/2023]
Abstract
ER stress signaling is linked to the pathophysiological and clinical disease manifestations in amyotrophic lateral sclerosis (ALS). Here, we have investigated ER stress-induced adaptive mechanisms in C9ORF72-ALS/FTD, focusing on uncovering early endogenous neuroprotective mechanisms and the crosstalk between pathological and adaptive responses in disease onset and progression. We provide evidence for the early onset of ER stress-mediated adaptive response in C9ORF72 patient-derived motoneurons (MNs), reflected by the elevated increase in GRP75 expression. These transiently increased GRP75 levels enhance ER-mitochondrial association, boosting mitochondrial function and sustaining cellular bioenergetics during the initial stage of disease, thereby counteracting early mitochondrial deficits. In C9orf72 rodent neurons, an abrupt reduction in GRP75 expression coincided with the onset of UPR, mitochondrial dysfunction and the emergence of PolyGA aggregates, which co-localize with GRP75. Similarly, the overexpression of PolyGA in WT cortical neurons or C9ORF72 patient-derived MNs led to the sequestration of GRP75 within PolyGA inclusions, resulting in mitochondrial calcium (Ca2+) uptake impairments. Corroborating these findings, we found that PolyGA aggregate-bearing human post-mortem C9ORF72 hippocampal dentate gyrus neurons not only display reduced expression of GRP75 but also exhibit GRP75 sequestration within inclusions. Sustaining high GRP75 expression in spinal C9orf72 rodent MNs specifically prevented ER stress, normalized mitochondrial function, abrogated PolyGA accumulation in spinal MNs, and ameliorated ALS-associated behavioral phenotype. Taken together, our results are in line with the notion that neurons in C9ORF72-ALS/FTD are particularly susceptible to ER-mitochondrial dysfunction and that GRP75 serves as a critical endogenous neuroprotective factor. This neuroprotective pathway, is eventually targeted by PolyGA, leading to GRP75 sequestration, and its subsequent loss of function at the MAM, compromising mitochondrial function and promoting disease onset.
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Damaged DNA Is an Early Event of Neurodegeneration in Induced Pluripotent Stem Cell-Derived Motoneurons with UBQLN2P497H Mutation. Int J Mol Sci 2022; 23:ijms231911333. [PMID: 36232630 PMCID: PMC9570184 DOI: 10.3390/ijms231911333] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2022] [Revised: 09/19/2022] [Accepted: 09/22/2022] [Indexed: 12/03/2022] Open
Abstract
Ubiquilin-2 (UBQLN2) mutations lead to familial amyotrophic lateral sclerosis (FALS)/and frontotemporal dementia (FTLD) through unknown mechanisms. The combination of iPSC technology and CRISPR-mediated genome editing technology can generate an iPSC-derived motor neuron (iPSC-MN) model with disease-relevant mutations, which results in increased opportunities for disease mechanism research and drug screening. In this study, we introduced a UBQLN2-P497H mutation into a healthy control iPSC line using CRISPR/Cas9, and differentiated into MNs to study the pathology of UBQLN2-related ALS. Our in vitro MN model faithfully recapitulated specific aspects of the disease, including MN apoptosis. Under sodium arsenite (SA) treatment, we found differences in the number and the size of UBQLN2+ inclusions in UBQLN2P497H MNs and wild-type (WT) MNs. We also observed cytoplasmic TAR DNA-binding protein (TARDBP, also known as TDP-43) aggregates in UBQLN2P497H MNs, but not in WT MNs, as well as the recruitment of TDP-43 into stress granules (SGs) upon SA treatment. We noted that UBQLN2-P497H mutation induced MNs DNA damage, which is an early event in UBQLN2-ALS. Additionally, DNA damage led to an increase in compensation for FUS, whereas UBQLN2-P497H mutation impaired this function. Therefore, FUS may be involved in DNA damage repair signaling.
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Fiskum V, Sandvig A, Sandvig I. Silencing of Activity During Hypoxia Improves Functional Outcomes in Motor Neuron Networks in vitro. Front Integr Neurosci 2021; 15:792863. [PMID: 34975426 PMCID: PMC8716921 DOI: 10.3389/fnint.2021.792863] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Accepted: 12/01/2021] [Indexed: 11/13/2022] Open
Abstract
The effects of hypoxia, or reduced oxygen supply, to brain tissue can be disastrous, leading to extensive loss of function. Deoxygenated tissue becomes unable to maintain healthy metabolism, which leads to increased production of reactive oxygen species (ROS) and loss of calcium homoeostasis, with damaging downstream effects. Neurons are a highly energy demanding cell type, and as such they are highly sensitive to reductions in oxygenation and some types of neurons such as motor neurons are even more susceptible to hypoxic damage. In addition to the immediate deleterious effects hypoxia can have on neurons, there can be delayed effects which lead to increased risk of developing neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), even if no immediate consequences are apparent. Furthermore, impairment of the function of various hypoxia-responsive factors has been shown to increase the risk of developing several neurodegenerative disorders. Longitudinal assessment of electrophysiological network activity is underutilised in assessing the effects of hypoxia on neurons and how their activity and communication change over time following a hypoxic challenge. This study utilised multielectrode arrays and motor neuron networks to study the response to hypoxia and the subsequent development of the neuronal activity over time, as well as the effect of silencing network activity during the hypoxic challenge. We found that motor neuron networks exposed to hypoxic challenge exhibited a delayed fluctuation in multiple network activity parameters compared to normoxic networks. Silencing of activity during the hypoxic challenge leads to maintained bursting activity, suggesting that functional outcomes are better maintained in these networks and that there are activity-dependent mechanisms involved in the network damage following hypoxia.
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Affiliation(s)
- Vegard Fiskum
- Department of Neuromedicine and Movement Science, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway
| | - Axel Sandvig
- Department of Neuromedicine and Movement Science, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway
- Department of Neurology, St. Olav’s Hospital, Trondheim University Hospital, Trondheim, Norway
- Department of Pharmacology and Clinical Neurosciences, Division of Neuro, Head, and Neck, Umeå University Hospital, Umeå, Sweden
- Department of Community Medicine and Rehabilitation, Umeå University, Umeå, Sweden
| | - Ioanna Sandvig
- Department of Neuromedicine and Movement Science, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway
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10
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Goyal S, Seth B, Chaturvedi RK. Polyphenols and Stem Cells for Neuroregeneration in Parkinson's Disease and Amyotrophic Lateral Sclerosis. Curr Pharm Des 2021; 28:806-828. [PMID: 34781865 DOI: 10.2174/1381612827666211115154450] [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: 04/05/2021] [Accepted: 11/02/2021] [Indexed: 11/22/2022]
Abstract
Parkinson's disease (PD) and Amyotrophic lateral sclerosis (ALS) are neurological disorders, pathologically characterized by chronic degeneration of dopaminergic neurons and motor neurons respectively. There is still no cure or effective treatment against the disease progression and most of the treatments are symptomatic. The present review offers an overview of the different factors involved in the pathogenesis of these diseases. Subsequently, we focused on the recent advanced studies of dietary polyphenols and stem cell therapies, which have made it possible to slow down the progression of neurodegeneration. To date, stem cells and different polyphenols have been used for the directional induction of neural stem cells into dopaminergic neurons and motor neurons. We have also discussed their involvement in the modulation of different signal transduction pathways and growth factor levels in various in vivo and in vitro studies. Likewise stem cells, polyphenols also exhibit the potential of neuroprotection by their anti-apoptotic, anti-inflammatory, anti-oxidant properties regulating the growth factors levels and molecular signaling events. Overall this review provides a detailed insight into recent strategies that promise the use of polyphenol with stem cell therapy for the possible treatment of PD and ALS.
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Affiliation(s)
- Shweta Goyal
- Developmental Toxicology Laboratory, Systems Toxicology and Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhavan, 31, Mahatma Gandhi Marg, Lucknow, Uttar Pradesh 226001. India
| | - Brashket Seth
- Developmental Toxicology Laboratory, Systems Toxicology and Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhavan, 31, Mahatma Gandhi Marg, Lucknow, Uttar Pradesh 226001. India
| | - Rajnish Kumar Chaturvedi
- Developmental Toxicology Laboratory, Systems Toxicology and Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhavan, 31, Mahatma Gandhi Marg, Lucknow, Uttar Pradesh 226001. India
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11
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Singh T, Jiao Y, Ferrando LM, Yablonska S, Li F, Horoszko EC, Lacomis D, Friedlander RM, Carlisle DL. Neuronal mitochondrial dysfunction in sporadic amyotrophic lateral sclerosis is developmentally regulated. Sci Rep 2021; 11:18916. [PMID: 34556702 PMCID: PMC8460779 DOI: 10.1038/s41598-021-97928-7] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Accepted: 09/01/2021] [Indexed: 02/08/2023] Open
Abstract
Amyotrophic lateral sclerosis is an adult-onset neurodegenerative disorder characterized by loss of motor neurons. Mitochondria are essential for neuronal survival but the developmental timing and mechanistic importance of mitochondrial dysfunction in sporadic ALS (sALS) neurons is not fully understood. We used human induced pluripotent stem cells and generated a developmental timeline by differentiating sALS iPSCs to neural progenitors and to motor neurons and comparing mitochondrial parameters with familial ALS (fALS) and control cells at each developmental stage. We report that sALS and fALS motor neurons have elevated reactive oxygen species levels, depolarized mitochondria, impaired oxidative phosphorylation, ATP loss and defective mitochondrial protein import compared with control motor neurons. This phenotype develops with differentiation into motor neurons, the affected cell type in ALS, and does not occur in the parental undifferentiated sALS cells or sALS neural progenitors. Our work demonstrates a developmentally regulated unifying mitochondrial phenotype between patient derived sALS and fALS motor neurons. The occurrence of a unifying mitochondrial phenotype suggests that mitochondrial etiology known to SOD1-fALS may applicable to sALS. Furthermore, our findings suggest that disease-modifying treatments focused on rescue of mitochondrial function may benefit both sALS and fALS patients.
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Affiliation(s)
- Tanisha Singh
- grid.21925.3d0000 0004 1936 9000Neuroapoptosis Laboratory, Department of Neurological Surgery, University of Pittsburgh, B400 Presbyterian Hospital, 200 Lothrop Street, Pittsburgh, PA 15213 USA
| | - Yuanyuan Jiao
- grid.21925.3d0000 0004 1936 9000Neuroapoptosis Laboratory, Department of Neurological Surgery, University of Pittsburgh, B400 Presbyterian Hospital, 200 Lothrop Street, Pittsburgh, PA 15213 USA
| | - Lisa M. Ferrando
- grid.21925.3d0000 0004 1936 9000Neuroapoptosis Laboratory, Department of Neurological Surgery, University of Pittsburgh, B400 Presbyterian Hospital, 200 Lothrop Street, Pittsburgh, PA 15213 USA
| | - Svitlana Yablonska
- grid.21925.3d0000 0004 1936 9000Neuroapoptosis Laboratory, Department of Neurological Surgery, University of Pittsburgh, B400 Presbyterian Hospital, 200 Lothrop Street, Pittsburgh, PA 15213 USA
| | - Fang Li
- grid.21925.3d0000 0004 1936 9000Neuroapoptosis Laboratory, Department of Neurological Surgery, University of Pittsburgh, B400 Presbyterian Hospital, 200 Lothrop Street, Pittsburgh, PA 15213 USA
| | - Emily C. Horoszko
- grid.21925.3d0000 0004 1936 9000Neuroapoptosis Laboratory, Department of Neurological Surgery, University of Pittsburgh, B400 Presbyterian Hospital, 200 Lothrop Street, Pittsburgh, PA 15213 USA
| | - David Lacomis
- grid.21925.3d0000 0004 1936 9000Departments of Neurology and Pathology, University of Pittsburgh, Pittsburgh, PA 15213 USA
| | - Robert M. Friedlander
- grid.21925.3d0000 0004 1936 9000Neuroapoptosis Laboratory, Department of Neurological Surgery, University of Pittsburgh, B400 Presbyterian Hospital, 200 Lothrop Street, Pittsburgh, PA 15213 USA
| | - Diane L. Carlisle
- grid.21925.3d0000 0004 1936 9000Neuroapoptosis Laboratory, Department of Neurological Surgery, University of Pittsburgh, B400 Presbyterian Hospital, 200 Lothrop Street, Pittsburgh, PA 15213 USA
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12
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Alam M, Yadav RK, Minj E, Tiwari A, Mehan S. Exploring Molecular Approaches in Amyotrophic Lateral Sclerosis: Drug Targets from Clinical and Pre-Clinical Findings. Curr Mol Pharmacol 2021; 14:263-280. [PMID: 32342825 DOI: 10.2174/1566524020666200427214356] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2019] [Revised: 12/24/2019] [Accepted: 12/26/2019] [Indexed: 11/22/2022]
Abstract
Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease (MND) characterized by the death of upper and lower motor neurons (corticospinal tract) in the motor cortex, basal ganglia, brain stem, and spinal cord. The patient experiences the sign and symptoms between 55 to 75 years of age, which include impaired motor movement, difficulty in speaking and swallowing, grip loss, muscle atrophy, spasticity, and sometimes associated with memory and cognitive impairments. Median survival is 3 to 5 years after diagnosis and 5 to 10% of the patients live for more than 10 years. The limited intervention of pharmacologically active compounds, that are used clinically, is majorly associated with the narrow therapeutic index. Pre-clinically established experimental models, where neurotoxin methyl mercury mimics the ALS like behavioural and neurochemical alterations in rodents associated with neuronal mitochondrial dysfunctions and downregulation of adenyl cyclase mediated cAMP/CREB, is the main pathological hallmark for the progression of ALS in central as well in the peripheral nervous system. Despite the considerable investigation into neuroprotection, it still constrains treatment choices to strong care and organization of ALS complications. Therefore, this current review specially targeted the investigation of clinical and pre-clinical features available for ALS to understand the pathogenic mechanisms and to explore the pharmacological interventions associated with the up-regulation of intracellular adenyl cyclase/cAMP/ CREB and activation of mitochondrial-ETC coenzyme-Q10 as a future drug target in the amelioration of ALS mediated motor neuronal dysfunctions.
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Affiliation(s)
- Mamtaj Alam
- Department of Pharmacology, ISF College of Pharmacy, Moga-142001, Punjab, India
| | - Rajeshwar K Yadav
- Department of Pharmacology, ISF College of Pharmacy, Moga-142001, Punjab, India
| | - Elizabeth Minj
- Department of Pharmacology, ISF College of Pharmacy, Moga-142001, Punjab, India
| | - Aarti Tiwari
- Department of Pharmacology, ISF College of Pharmacy, Moga-142001, Punjab, India
| | - Sidharth Mehan
- Department of Pharmacology, ISF College of Pharmacy, Moga-142001, Punjab, India
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13
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Zhao A, Pan Y, Cai S. Patient-Specific Cells for Modeling and Decoding Amyotrophic Lateral Sclerosis: Advances and Challenges. Stem Cell Rev Rep 2021; 16:482-502. [PMID: 31916190 DOI: 10.1007/s12015-019-09946-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Motor neuron loss or degeneration is the typical characteristic of amyotrophic lateral sclerosis (ALS), which often leads to weakness, paralysis, or even death. The underlying mechanisms of motor neuron degeneration and ALS progression remain elusive, and there is no effective treatment for ALS. The advances of stem cells and reprogramming techniques has made it possible to generate patient-specific motor neurons as cell models for studying disease mechanisms and drug discovery. This review comprehensively discusses recent approaches to generate motor neurons from stem cells and somatic cells and highlights the application of induced motor neurons to modeling ALS diseases, dissecting the pathogenesis, and screening new drugs. New perspectives are also discussed on generating patient-specific motor neuron subtypes that are affected by ALS or creating 3D spinal cord organoid models for better recapitulating and understanding ALS.
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Affiliation(s)
- Andong Zhao
- Health Science Center, Shenzhen University, Shenzhen, 518060, China
| | - Yu Pan
- Department of Trauma and Orthopedics, The 2nd Affiliated Hospital of Shenzhen University, The Affiliated Baoan Hospital of Southern Medical University, Shenzhen, 518101, China.
| | - Sa Cai
- Health Science Center, Shenzhen University, Shenzhen, 518060, China.
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14
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Wood A, Gurfinkel Y, Polain N, Lamont W, Lyn Rea S. Molecular Mechanisms Underlying TDP-43 Pathology in Cellular and Animal Models of ALS and FTLD. Int J Mol Sci 2021; 22:4705. [PMID: 33946763 PMCID: PMC8125728 DOI: 10.3390/ijms22094705] [Citation(s) in RCA: 59] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Revised: 04/22/2021] [Accepted: 04/28/2021] [Indexed: 02/03/2023] Open
Abstract
Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are neurodegenerative disorders that exist on a disease spectrum due to pathological, clinical and genetic overlap. In up to 97% of ALS cases and ~50% of FTLD cases, the primary pathological protein observed in affected tissues is TDP-43, which is hyperphosphorylated, ubiquitinated and cleaved. The TDP-43 is observed in aggregates that are abnormally located in the cytoplasm. The pathogenicity of TDP-43 cytoplasmic aggregates may be linked with both a loss of nuclear function and a gain of toxic functions. The cellular processes involved in ALS and FTLD disease pathogenesis include changes to RNA splicing, abnormal stress granules, mitochondrial dysfunction, impairments to axonal transport and autophagy, abnormal neuromuscular junctions, endoplasmic reticulum stress and the subsequent induction of the unfolded protein response. Here, we review and discuss the evidence for alterations to these processes that have been reported in cellular and animal models of TDP-43 proteinopathy.
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Affiliation(s)
- Alistair Wood
- School of Molecular Science, University of Western Australia, Nedlands 6009, Australia;
- Centre for Molecular Medicine and Innovative Therapeutics, Murdoch University, Health Research Building, Discovery Way, Murdoch 6150, Australia; (Y.G.); (N.P.)
| | - Yuval Gurfinkel
- Centre for Molecular Medicine and Innovative Therapeutics, Murdoch University, Health Research Building, Discovery Way, Murdoch 6150, Australia; (Y.G.); (N.P.)
- Perron Institute for Neurological and Translational Science, Centre for Neuromuscular and Neurological Disorders, University of Western Australia, Nedlands 6009, Australia;
| | - Nicole Polain
- Centre for Molecular Medicine and Innovative Therapeutics, Murdoch University, Health Research Building, Discovery Way, Murdoch 6150, Australia; (Y.G.); (N.P.)
| | - Wesley Lamont
- Perron Institute for Neurological and Translational Science, Centre for Neuromuscular and Neurological Disorders, University of Western Australia, Nedlands 6009, Australia;
| | - Sarah Lyn Rea
- Centre for Molecular Medicine and Innovative Therapeutics, Murdoch University, Health Research Building, Discovery Way, Murdoch 6150, Australia; (Y.G.); (N.P.)
- Hub for Immersive Visualisation and eResearch, Curtin University, Bentley 6102, Australia
- Harry Perkins Institute of Medical Research, Centre for Medical Research, University of Western Australia, Nedlands 6009, Australia
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15
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Tedeschi V, Petrozziello T, Secondo A. Ca 2+ dysregulation in the pathogenesis of amyotrophic lateral sclerosis. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2021; 363:21-47. [PMID: 34392931 DOI: 10.1016/bs.ircmb.2021.02.014] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/12/2023]
Abstract
Amyotrophic Lateral Sclerosis (ALS) is a devastating neurodegenerative disease without appropriate cure. One of the main reasons for the lack of a proper pharmacotherapy in ALS is the narrow knowledge on the molecular causes of the disease. In this respect, the identification of dysfunctional pathways in ALS is now considered a critical medical need. Among the causative factors involved in ALS, Ca2+ dysregulation is one of the most important pathogenetic mechanisms of the disease. Of note, Ca2+ dysfunction may induce, directly or indirectly, motor neuron degeneration and loss. Interestingly, both familial (fALS) and sporadic ALS (sALS) share the progressive dysregulation of Ca2+ homeostasis as a common noxious mechanism. Mechanicistically, Ca2+ dysfunction involves both plasma membrane and intracellular mechanisms, including AMPA receptor (AMPAR)-mediated excitotoxicity, voltage-gated Ca2+ channels (VGCCs) and Ca2+ transporter dysregulation, endoplasmic reticulum (ER) Ca2+ deregulation, mitochondria-associated ER membranes (MAMs) dysfunction, lysosomal Ca2+ leak, etc. Here, a comprehensive analysis of the main pathways involved in the dysregulation of Ca2+ homeostasis has been reported with the aim to focus the attention on new putative druggable targets.
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Affiliation(s)
- Valentina Tedeschi
- Division of Pharmacology, Department of Neuroscience, Reproductive and Odontostomatological Sciences, School of Medicine, "Federico II" University of Naples, Naples, Italy
| | - Tiziana Petrozziello
- Division of Pharmacology, Department of Neuroscience, Reproductive and Odontostomatological Sciences, School of Medicine, "Federico II" University of Naples, Naples, Italy
| | - Agnese Secondo
- Division of Pharmacology, Department of Neuroscience, Reproductive and Odontostomatological Sciences, School of Medicine, "Federico II" University of Naples, Naples, Italy.
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16
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Finkbeiner S. Functional genomics, genetic risk profiling and cell phenotypes in neurodegenerative disease. Neurobiol Dis 2020; 146:105088. [PMID: 32977020 PMCID: PMC7686089 DOI: 10.1016/j.nbd.2020.105088] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Revised: 09/11/2020] [Accepted: 09/18/2020] [Indexed: 12/03/2022] Open
Abstract
Human genetics provides unbiased insights into the causes of human disease, which can be used to create a foundation for effective ways to more accurately diagnose patients, stratify patients for more successful clinical trials, discover and develop new therapies, and ultimately help patients choose the safest and most promising therapeutic option based on their risk profile. But the process for translating basic observations from human genetics studies into pathogenic disease mechanisms and treatments is laborious and complex, and this challenge has particularly slowed the development of interventions for neurodegenerative disease. In this review, we discuss the many steps in the process, the important considerations at each stage, and some of the latest tools and technologies that are available to help investigators translate insights from human genetics into diagnostic and therapeutic strategies that will lead to the sort of advances in clinical care that make a difference for patients.
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Affiliation(s)
- Steven Finkbeiner
- Center for Systems and Therapeutics, USA; Taube/Koret Center for Neurodegenerative Disease Research, Gladstone Institutes, San Francisco, CA 94158, USA; Departments of Neurology and Physiology, University of Califorina, San Francisco, CA 94158, USA.
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17
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CYP1A2 rs762551 polymorphism and risk for amyotrophic lateral sclerosis. Neurol Sci 2020; 42:175-182. [PMID: 32592103 DOI: 10.1007/s10072-020-04535-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2020] [Accepted: 06/21/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND Genetic variability is considered to confer susceptibility to amyotrophic lateral sclerosis (ALS). Oxidative stress is a significant contributor to ALS-related neurodegeneration, and it is regulated by cytochromes P450 (CYPs), such as CYP1A2; these are responsible for the oxidative metabolism of both exogenous and endogenous substrates in the brain, subsequently impacting ALS. The function of CYP1A2 is largely affected by genetic variability; however, the impact of CYP1A2 polymorphisms in ALS remains underinvestigated. OBJECTIVE This study aims to examine the possible association of ALS with the CYP1A2 rs762551 polymorphism, which codes for the high inducibility form of the enzyme. METHODS One hundred and fifty-five patients with sporadic ALS and 155 healthy controls were genotyped for the CYP1A2 rs762551. Statistical testing for the association of CYP1A2 rs762551 with risk for ALS was performed using SNPstats. RESULTS The CYP1A2 rs762551 C allele was associated with a decreased risk of ALS development. In the subgroup analysis according to the ALS site of onset, an association between CYP1A2 rs762551 and limb and bulbar onset of ALS was shown. Cox proportional-hazard regression analyses revealed a significant effect of the CYP1A2 rs762551 on the age of onset of ALS. CONCLUSIONS Based on our results, a primarily potential link between the CYP1A2 rs762551 polymorphism and ALS risk could exist.
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18
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Pessah IN, Lein PJ, Seegal RF, Sagiv SK. Neurotoxicity of polychlorinated biphenyls and related organohalogens. Acta Neuropathol 2019; 138:363-387. [PMID: 30976975 PMCID: PMC6708608 DOI: 10.1007/s00401-019-01978-1] [Citation(s) in RCA: 122] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2018] [Revised: 02/12/2019] [Accepted: 02/19/2019] [Indexed: 01/28/2023]
Abstract
Halogenated organic compounds are pervasive in natural and built environments. Despite restrictions on the production of many of these compounds in most parts of the world through the Stockholm Convention on Persistent Organic Pollutants (POPs), many "legacy" compounds, including polychlorinated biphenyls (PCBs), are routinely detected in human tissues where they continue to pose significant health risks to highly exposed and susceptible populations. A major concern is developmental neurotoxicity, although impacts on neurodegenerative outcomes have also been noted. Here, we review human studies of prenatal and adult exposures to PCBs and describe the state of knowledge regarding outcomes across domains related to cognition (e.g., IQ, language, memory, learning), attention, behavioral regulation and executive function, and social behavior, including traits related to attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorders (ASD). We also review current understanding of molecular mechanisms underpinning these associations, with a focus on dopaminergic neurotransmission, thyroid hormone disruption, calcium dyshomeostasis, and oxidative stress. Finally, we briefly consider contemporary sources of organohalogens that may pose human health risks via mechanisms of neurotoxicity common to those ascribed to PCBs.
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Affiliation(s)
- Isaac N Pessah
- Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, 1089 VM3B, Davis, CA, 95616, USA.
| | - Pamela J Lein
- Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, 1089 VM3B, Davis, CA, 95616, USA
| | - Richard F Seegal
- Professor Emeritus, School of Public Health, University at Albany, Rensselaer, NY, USA
| | - Sharon K Sagiv
- Center for Environmental Research and Children's Health (CERCH), School of Public Health, University of California, Berkeley, CA, USA
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19
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McGurk L, Rifai OM, Bonini NM. Poly(ADP-Ribosylation) in Age-Related Neurological Disease. Trends Genet 2019; 35:601-613. [PMID: 31182245 DOI: 10.1016/j.tig.2019.05.004] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2019] [Revised: 05/14/2019] [Accepted: 05/15/2019] [Indexed: 12/14/2022]
Abstract
A central and causative feature of age-related neurodegenerative disease is the deposition of misfolded proteins in the brain. To devise novel approaches to treatment, regulatory pathways that modulate these aggregation-prone proteins must be defined. One such pathway is post-translational modification by the addition of poly(ADP-ribose) (PAR), which promotes protein recruitment and localization in several cellular contexts. Mounting evidence implicates PAR in seeding the abnormal localization and accumulation of proteins that are causative of neurodegenerative disease. Inhibitors of PAR polymerase (PARP) activity have been developed as cancer therapeutics, raising the possibility that they could be used to treat neurodegenerative disease. We focus on pathways regulated by PAR in neurodegenerative disease, with emphasis on amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD).
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Affiliation(s)
- Leeanne McGurk
- Department of Biology, University of Pennsylvania, Philadelphia, PA 19104, USA.
| | - Olivia M Rifai
- Department of Biology, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Nancy M Bonini
- Department of Biology, University of Pennsylvania, Philadelphia, PA 19104, USA.
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20
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TDP-43 induces mitochondrial damage and activates the mitochondrial unfolded protein response. PLoS Genet 2019; 15:e1007947. [PMID: 31100073 PMCID: PMC6524796 DOI: 10.1371/journal.pgen.1007947] [Citation(s) in RCA: 156] [Impact Index Per Article: 26.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2018] [Accepted: 01/08/2019] [Indexed: 02/07/2023] Open
Abstract
Mutations in or dys-regulation of the TDP-43 gene have been associated with TDP-43 proteinopathy, a spectrum of neurodegenerative diseases including Frontotemporal Lobar Degeneration (FTLD) and Amyotrophic Lateral Sclerosis (ALS). The underlying molecular and cellular defects, however, remain unclear. Here, we report a systematic study combining analyses of patient brain samples with cellular and animal models for TDP-43 proteinopathy. Electron microscopy (EM) analyses of patient samples revealed prominent mitochondrial impairment, including abnormal cristae and a loss of cristae; these ultrastructural changes were consistently observed in both cellular and animal models of TDP-43 proteinopathy. In these models, increased TDP-43 expression induced mitochondrial dysfunction, including decreased mitochondrial membrane potential and elevated production of reactive oxygen species (ROS). TDP-43 expression suppressed mitochondrial complex I activity and reduced mitochondrial ATP synthesis. Importantly, TDP-43 activated the mitochondrial unfolded protein response (UPRmt) in both cellular and animal models. Down-regulating mitochondrial protease LonP1 increased mitochondrial TDP-43 levels and exacerbated TDP-43-induced mitochondrial damage as well as neurodegeneration. Together, our results demonstrate that TDP-43 induced mitochondrial impairment is a critical aspect in TDP-43 proteinopathy. Our work has not only uncovered a previously unknown role of LonP1 in regulating mitochondrial TDP-43 levels, but also advanced our understanding of the pathogenic mechanisms for TDP-43 proteinopathy. Our study suggests that blocking or reversing mitochondrial damage may provide a potential therapeutic approach to these devastating diseases. TDP-43 proteinopathy is a group of fatal neurological diseases. Here, we report a systematic examination of the role of mitochondrial damage in TDP-43 proteinopathy using patient brain tissues, as well as cellular and animal models. Our data show that TDP-43 induces severe mitochondrial damage, accompanied by activation of UPRmt in both cellular and animal models of TDP-43 proteinopathy. LonP1, one of the key mitochondrial proteases in UPRmt, protects against TDP-43 induced cytotoxicity and neurodegeneration. Our study uncovers LonP1 as a modifier gene for TDP-43 proteinopathy and suggests protecting against or reversing mitochondrial damage as a potential therapeutic approach to these neurodegenerative disorders.
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21
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Andrés-Benito P, Gelpi E, Povedano M, Ausín K, Fernández-Irigoyen J, Santamaría E, Ferrer I. Combined Transcriptomics and Proteomics in Frontal Cortex Area 8 in Frontotemporal Lobar Degeneration Linked to C9ORF72 Expansion. J Alzheimers Dis 2019; 68:1287-1307. [DOI: 10.3233/jad-181123] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Affiliation(s)
- Pol Andrés-Benito
- Neuropathology, Pathologic Anatomy Service, Bellvitge University Hospital - Bellvitge Biomedical Research Institute (IDIBELL), Hospitalet de Llobregat, Spain
- Biomedical Network Research Center on Neurodegenerative Diseases (CIBERNED), Institute of Health Carlos III, Hospitalet de Llobregat, Spain
| | - Ellen Gelpi
- Neurological Tissue Bank of the Biobanc-Hospital Clínic-Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
- Institute of Neurology, Medical University of Vienna, Vienna, Austria
| | - Mónica Povedano
- Functional Unit of Amyotrophic Lateral Sclerosis (UFELA), Service of Neurology, Bellvitge University Hospital, Hospitalet de Llobregat, Spain
| | - Karina Ausín
- IDISNA, Navarra Institute for Health Research, Pamplona, Spain
- Clinical Neuroproteomics group and Proteored-ISCIII, Proteomics Unit, Navarrabiomed, Department of Health, Public University of Navarra, Pamplona, Spain
| | - Joaquín Fernández-Irigoyen
- IDISNA, Navarra Institute for Health Research, Pamplona, Spain
- Clinical Neuroproteomics group and Proteored-ISCIII, Proteomics Unit, Navarrabiomed, Department of Health, Public University of Navarra, Pamplona, Spain
| | - Enrique Santamaría
- IDISNA, Navarra Institute for Health Research, Pamplona, Spain
- Clinical Neuroproteomics group and Proteored-ISCIII, Proteomics Unit, Navarrabiomed, Department of Health, Public University of Navarra, Pamplona, Spain
| | - Isidro Ferrer
- Neuropathology, Pathologic Anatomy Service, Bellvitge University Hospital - Bellvitge Biomedical Research Institute (IDIBELL), Hospitalet de Llobregat, Spain
- Biomedical Network Research Center on Neurodegenerative Diseases (CIBERNED), Institute of Health Carlos III, Hospitalet de Llobregat, Spain
- Department of Pathology and Experimental Therapeutics, University of Barcelona, Hospitalet de Llobregat, Spain
- Institute of Neurosciences, University of Barcelona, Barcelona, Spain
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22
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Zhou J, Li A, Li X, Yi J. Dysregulated mitochondrial Ca 2+ and ROS signaling in skeletal muscle of ALS mouse model. Arch Biochem Biophys 2019; 663:249-258. [PMID: 30682329 PMCID: PMC6506190 DOI: 10.1016/j.abb.2019.01.024] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2018] [Revised: 12/24/2018] [Accepted: 01/18/2019] [Indexed: 12/12/2022]
Abstract
Amyotrophic lateral sclerosis (ALS) is a devastating neuromuscular disease characterized by motor neuron loss and prominent skeletal muscle wasting. Despite more than one hundred years of research efforts, the pathogenic mechanisms underlying neuromuscular degeneration in ALS remain elusive. While the death of motor neuron is a defining hallmark of ALS, accumulated evidences suggested that in addition to being a victim of motor neuron axonal withdrawal, the intrinsic skeletal muscle degeneration may also actively contribute to ALS disease pathogenesis and progression. Examination of spinal cord and muscle autopsy/biopsy samples of ALS patients revealed similar mitochondrial abnormalities in morphology, quantity and disposition, which are accompanied by defective mitochondrial respiratory chain complex and elevated oxidative stress. Detailing the molecular/cellular mechanisms and the role of mitochondrial dysfunction in ALS relies on ALS animal model studies. This review article discusses the dysregulated mitochondrial Ca2+ and reactive oxygen species (ROS) signaling revealed in live skeletal muscle derived from ALS mouse models, and a potential role of the vicious cycle formed between the dysregulated mitochondrial Ca2+ signaling and excessive ROS production in promoting muscle wasting during ALS progression.
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Affiliation(s)
- Jingsong Zhou
- Kansas City University of Medicine and Bioscience, Kansas City, MO 64106, USA; College of Nursing and Health Innovation, University of Texas at Arlington, Arlington, TX 76019, USA.
| | - Ang Li
- Kansas City University of Medicine and Bioscience, Kansas City, MO 64106, USA; College of Nursing and Health Innovation, University of Texas at Arlington, Arlington, TX 76019, USA
| | - Xuejun Li
- Kansas City University of Medicine and Bioscience, Kansas City, MO 64106, USA; College of Nursing and Health Innovation, University of Texas at Arlington, Arlington, TX 76019, USA
| | - Jianxun Yi
- Kansas City University of Medicine and Bioscience, Kansas City, MO 64106, USA; College of Nursing and Health Innovation, University of Texas at Arlington, Arlington, TX 76019, USA.
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23
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Veyrat-Durebex C, Bris C, Codron P, Bocca C, Chupin S, Corcia P, Vourc'h P, Hergesheimer R, Cassereau J, Funalot B, Andres CR, Lenaers G, Couratier P, Reynier P, Blasco H. Metabo-lipidomics of Fibroblasts and Mitochondrial-Endoplasmic Reticulum Extracts from ALS Patients Shows Alterations in Purine, Pyrimidine, Energetic, and Phospholipid Metabolisms. Mol Neurobiol 2019; 56:5780-5791. [PMID: 30680691 DOI: 10.1007/s12035-019-1484-7] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2018] [Accepted: 01/10/2019] [Indexed: 12/16/2022]
Abstract
Amyotrophic lateral sclerosis (ALS) is characterized by a wide metabolic remodeling, as shown by recent metabolomics and lipidomics studies performed in samples from patient cohorts and experimental animal models. Here, we explored the metabolome and lipidome of fibroblasts from sporadic ALS patients (n = 13) comparatively to age- and sex-matched controls (n = 11), and the subcellular fraction containing the mitochondria and endoplasmic reticulum (mito-ER), given that mitochondrial dysfunctions and ER stress are important features of ALS patho-mechanisms. We also assessed the mitochondrial oxidative respiration and the mitochondrial genomic (mtDNA) sequence, although without yielding significant differences. Compared to controls, ALS fibroblasts did not exhibit a mitochondrial respiration defect nor an increased proportion of mitochondrial DNA mutations. In addition, non-targeted metabolomics and lipidomics analyses identified 124 and 127 metabolites, and 328 and 220 lipids in whole cells and the mito-ER fractions, respectively, along with partial least-squares-discriminant analysis (PLS-DA) models being systematically highly predictive of the disease. The most discriminant metabolomic features were the alteration of purine, pyrimidine, and energetic metabolisms, suggestive of oxidative stress and of pro-inflammatory status. The most important lipidomic feature in the mito-ER fraction was the disturbance of phosphatidylcholine PC (36:4p) levels, which we had previously reported in the cerebrospinal fluid of ALS patients and in the brain from an ALS mouse model. Thus, our results reveal that fibroblasts from sporadic ALS patients share common metabolic remodeling, consistent with other metabolic studies performed in ALS, opening perspectives for further exploration in this cellular model in ALS.
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Affiliation(s)
- Charlotte Veyrat-Durebex
- Département de Biochimie et Génétique, CHU d'Angers, Angers, France. .,Unité Mixte de Recherche MITOVASC, CNRS 6015-INSERM 1083, Université d'Angers, Angers, France. .,Laboratoire de Biochimie et Biologie Moléculaire, CHRU Hôpital Bretonneau, 2, Bd Tonnellé, 37044, Tours, France.
| | - Céline Bris
- Département de Biochimie et Génétique, CHU d'Angers, Angers, France.,Unité Mixte de Recherche MITOVASC, CNRS 6015-INSERM 1083, Université d'Angers, Angers, France
| | - Philippe Codron
- Unité Mixte de Recherche MITOVASC, CNRS 6015-INSERM 1083, Université d'Angers, Angers, France.,Centre de Ressources et de Compétences SLA, Service de Neurologie, CHU Angers, Angers, France
| | - Cinzia Bocca
- Unité Mixte de Recherche MITOVASC, CNRS 6015-INSERM 1083, Université d'Angers, Angers, France
| | - Stéphanie Chupin
- Département de Biochimie et Génétique, CHU d'Angers, Angers, France
| | - Philippe Corcia
- Université de Tours, Inserm U1253, Tours, France.,Centre de Référence SLA, Service de Neurologie, CHRU Bretonneau, Tours, France.,Fédération des CRCSLA Tours et Limoges, LITORALS, Tours, France
| | - Patrick Vourc'h
- Laboratoire de Biochimie et Biologie Moléculaire, CHRU Hôpital Bretonneau, 2, Bd Tonnellé, 37044, Tours, France.,Université de Tours, Inserm U1253, Tours, France
| | | | - Julien Cassereau
- Unité Mixte de Recherche MITOVASC, CNRS 6015-INSERM 1083, Université d'Angers, Angers, France.,Centre de Ressources et de Compétences SLA, Service de Neurologie, CHU Angers, Angers, France
| | - Benoit Funalot
- Fédération des CRCSLA Tours et Limoges, LITORALS, Tours, France
| | - Christian R Andres
- Laboratoire de Biochimie et Biologie Moléculaire, CHRU Hôpital Bretonneau, 2, Bd Tonnellé, 37044, Tours, France.,Université de Tours, Inserm U1253, Tours, France
| | - Guy Lenaers
- Unité Mixte de Recherche MITOVASC, CNRS 6015-INSERM 1083, Université d'Angers, Angers, France
| | | | - Pascal Reynier
- Département de Biochimie et Génétique, CHU d'Angers, Angers, France.,Unité Mixte de Recherche MITOVASC, CNRS 6015-INSERM 1083, Université d'Angers, Angers, France
| | - Hélène Blasco
- Unité Mixte de Recherche MITOVASC, CNRS 6015-INSERM 1083, Université d'Angers, Angers, France. .,Laboratoire de Biochimie et Biologie Moléculaire, CHRU Hôpital Bretonneau, 2, Bd Tonnellé, 37044, Tours, France. .,Université de Tours, Inserm U1253, Tours, France.
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24
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Secondo A, Bagetta G, Amantea D. On the Role of Store-Operated Calcium Entry in Acute and Chronic Neurodegenerative Diseases. Front Mol Neurosci 2018; 11:87. [PMID: 29623030 PMCID: PMC5874322 DOI: 10.3389/fnmol.2018.00087] [Citation(s) in RCA: 71] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2018] [Accepted: 03/06/2018] [Indexed: 12/22/2022] Open
Abstract
In both excitable and non-excitable cells, calcium (Ca2+) signals are maintained by a highly integrated process involving store-operated Ca2+ entry (SOCE), namely the opening of plasma membrane (PM) Ca2+ channels following the release of Ca2+ from intracellular stores. Upon depletion of Ca2+ store, the stromal interaction molecule (STIM) senses Ca2+ level reduction and migrates from endoplasmic reticulum (ER)-like sites to the PM where it activates the channel proteins Orai and/or the transient receptor potential channels (TRPC) prompting Ca2+ refilling. Accumulating evidence suggests that SOCE dysregulation may trigger perturbation of intracellular Ca2+ signaling in neurons, glia or hematopoietic cells, thus participating to the pathogenesis of diverse neurodegenerative diseases. Under acute conditions, such as ischemic stroke, neuronal SOCE can either re-establish Ca2+ homeostasis or mediate Ca2+ overload, thus providing a non-excitotoxic mechanism of ischemic neuronal death. The dualistic role of SOCE in brain ischemia is further underscored by the evidence that it also participates to endothelial restoration and to the stabilization of intravascular thrombi. In Parkinson's disease (PD) models, loss of SOCE triggers ER stress and dysfunction/degeneration of dopaminergic neurons. Disruption of neuronal SOCE also underlies Alzheimer's disease (AD) pathogenesis, since both in genetic mouse models and in human sporadic AD brain samples, reduced SOCE contributes to synaptic loss and cognitive decline. Unlike the AD setting, in the striatum from Huntington's disease (HD) transgenic mice, an increased STIM2 expression causes elevated synaptic SOCE that was suggested to underlie synaptic loss in medium spiny neurons. Thus, pharmacological inhibition of SOCE is beneficial to synapse maintenance in HD models, whereas the same approach may be anticipated to be detrimental to cortical and hippocampal pyramidal neurons. On the other hand, up-regulation of SOCE may be beneficial during AD. These intriguing findings highlight the importance of further mechanistic studies to dissect the molecular pathways, and their corresponding targets, involved in synaptic dysfunction and neuronal loss during aging and neurodegenerative diseases.
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Affiliation(s)
- Agnese Secondo
- Division of Pharmacology, Department of Neuroscience, Reproductive and Odontostomatological Sciences, University of Naples Federico II, Napoli, Italy
| | - Giacinto Bagetta
- Department of Pharmacy, Health and Nutritional Sciences, Section of Preclinical and Translational Pharmacology, University of Calabria, Cosenza, Italy
| | - Diana Amantea
- Department of Pharmacy, Health and Nutritional Sciences, Section of Preclinical and Translational Pharmacology, University of Calabria, Cosenza, Italy
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25
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Guo W, Fumagalli L, Prior R, Van Den Bosch L. Current Advances and Limitations in Modeling ALS/FTD in a Dish Using Induced Pluripotent Stem Cells. Front Neurosci 2017; 11:671. [PMID: 29326542 PMCID: PMC5733489 DOI: 10.3389/fnins.2017.00671] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2017] [Accepted: 11/20/2017] [Indexed: 12/11/2022] Open
Abstract
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two age-dependent multifactorial neurodegenerative disorders, which are typically characterized by the selective death of motor neurons and cerebral cortex neurons, respectively. These two diseases share many clinical, genetic and pathological aspects. During the past decade, cell reprogramming technologies enabled researchers to generate human induced pluripotent stem cells (iPSCs) from somatic cells. This resulted in the unique opportunity to obtain specific neuronal and non-neuronal cell types from patients which could be used for basic research. Moreover, these in vitro models can mimic not only the familial forms of ALS/FTD, but also sporadic cases without known genetic cause. At present, there have been extensive technical advances in the generation of iPSCs, as well as in the differentiation procedures to obtain iPSC-derived motor neurons, cortical neurons and non-neuronal cells. The major challenge at this moment is to determine whether these iPSC-derived cells show relevant phenotypes that recapitulate complex diseases. In this review, we will summarize the work related to iPSC models of ALS and FTD. In addition, we will discuss potential drawbacks and solutions for establishing more trustworthy iPSC models for both ALS and FTD.
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Affiliation(s)
- Wenting Guo
- KU Leuven-Department of Neurosciences, Experimental Neurology and Leuven Institute for Neuroscience and Disease, Leuven, Belgium.,Laboratory of Neurobiology, VIB & KU Leuven Center for Brain & Disease Research, Leuven, Belgium
| | - Laura Fumagalli
- KU Leuven-Department of Neurosciences, Experimental Neurology and Leuven Institute for Neuroscience and Disease, Leuven, Belgium.,Laboratory of Neurobiology, VIB & KU Leuven Center for Brain & Disease Research, Leuven, Belgium
| | - Robert Prior
- KU Leuven-Department of Neurosciences, Experimental Neurology and Leuven Institute for Neuroscience and Disease, Leuven, Belgium.,Laboratory of Neurobiology, VIB & KU Leuven Center for Brain & Disease Research, Leuven, Belgium
| | - Ludo Van Den Bosch
- KU Leuven-Department of Neurosciences, Experimental Neurology and Leuven Institute for Neuroscience and Disease, Leuven, Belgium.,Laboratory of Neurobiology, VIB & KU Leuven Center for Brain & Disease Research, Leuven, Belgium
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26
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Maguire G. Amyotrophic lateral sclerosis as a protein level, non-genomic disease: Therapy with S2RM exosome released molecules. World J Stem Cells 2017; 9:187-202. [PMID: 29312526 PMCID: PMC5745587 DOI: 10.4252/wjsc.v9.i11.187] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2017] [Revised: 08/10/2017] [Accepted: 09/04/2017] [Indexed: 02/06/2023] Open
Abstract
Amyotrophic lateral sclerosis (ALS) is a rapidly progressing neurodegenerative disease that leads to death. No effective treatments are currently available. Based on data from epidemiological, etiological, laboratory, and clinical studies, I offer a new way of thinking about ALS and its treatment. This paper describes a host of extrinsic factors, including the exposome, that disrupt the extracellular matrix and protein function such that a spreading, prion-like disease leads to neurodegeneration in the motor tracts. A treatment regimen is described using the stem cell released molecules from a number of types of adult stem cells to provide tissue dependent molecules that restore homeostasis, including proteostasis, in the ALS patient. Because stem cells themselves as a therapeutic are cumbersome and expensive, and when implanted in a host cause aging of the host tissue and often fail to engraft or remain viable, only the S2RM molecules are used. Rebuilding of the extracellular matrix and repair of the dysfunctional proteins in the ALS patient ensues.
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Affiliation(s)
- Greg Maguire
- BioRegenerative Sciences, Inc., La Jolla, CA 92037, United States
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27
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Veyrat-Durebex C, Bocca C, Chupin S, Kouassi Nzoughet J, Simard G, Lenaers G, Reynier P, Blasco H. Metabolomics and Lipidomics Profiling of a Combined Mitochondrial Plus Endoplasmic Reticulum Fraction of Human Fibroblasts: A Robust Tool for Clinical Studies. J Proteome Res 2017; 17:745-750. [PMID: 29111762 DOI: 10.1021/acs.jproteome.7b00637] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Mitochondria and endoplasmic reticulum (ER) are physically and functionally connected. This close interaction, via mitochondria-associated membranes, is increasingly explored and supports the importance of studying these two organelles as a whole. Metabolomics and lipidomics are powerful approaches for the exploration of metabolic pathways that may be useful to provide deeper information on these organelles' functions, dysfunctions, and interactions. We developed a quick and simple experimental procedure for the purification of a mitochondria-ER fraction from human fibroblasts. We applied combined metabolomics and lipidomics analyses by mass spectrometry with excellent reproducibility. Seventy-two metabolites and 418 complex lipids were detected with a mean coefficient of variation around 12%, among which many were specific to the mitochondrial metabolism. Thus this strategy based on robust mitochondria-ER extraction and "omics" combination will be useful for investigating the pathophysiology of complex diseases.
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Affiliation(s)
- Charlotte Veyrat-Durebex
- Département de Biochimie et Génétique, Centre Hospitalier Universitaire , 49933 Angers, France.,Equipe Mitolab, Institut MITOVASC, UMR CNRS 6015, INSERM 1083, Université d'Angers , 49933 Angers, France
| | - Cinzia Bocca
- Equipe Mitolab, Institut MITOVASC, UMR CNRS 6015, INSERM 1083, Université d'Angers , 49933 Angers, France
| | - Stéphanie Chupin
- Département de Biochimie et Génétique, Centre Hospitalier Universitaire , 49933 Angers, France
| | - Judith Kouassi Nzoughet
- Equipe Mitolab, Institut MITOVASC, UMR CNRS 6015, INSERM 1083, Université d'Angers , 49933 Angers, France
| | - Gilles Simard
- Département de Biochimie et Génétique, Centre Hospitalier Universitaire , 49933 Angers, France
| | - Guy Lenaers
- Equipe Mitolab, Institut MITOVASC, UMR CNRS 6015, INSERM 1083, Université d'Angers , 49933 Angers, France
| | - Pascal Reynier
- Département de Biochimie et Génétique, Centre Hospitalier Universitaire , 49933 Angers, France.,Equipe Mitolab, Institut MITOVASC, UMR CNRS 6015, INSERM 1083, Université d'Angers , 49933 Angers, France
| | - Hélène Blasco
- Equipe Mitolab, Institut MITOVASC, UMR CNRS 6015, INSERM 1083, Université d'Angers , 49933 Angers, France.,Université François-Rabelais , INSERM U930, 37000 Tours, France.,Laboratoire de Biochimie et Biologie Moléculaire, CHRU de Tours , 37044 Tours, France
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28
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Martin-Jiménez CA, García-Vega Á, Cabezas R, Aliev G, Echeverria V, González J, Barreto GE. Astrocytes and endoplasmic reticulum stress: A bridge between obesity and neurodegenerative diseases. Prog Neurobiol 2017; 158:45-68. [DOI: 10.1016/j.pneurobio.2017.08.001] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2017] [Revised: 05/22/2017] [Accepted: 08/04/2017] [Indexed: 12/13/2022]
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29
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Zeineddine R, Farrawell NE, Lambert-Smith IA, Yerbury JJ. Addition of exogenous SOD1 aggregates causes TDP-43 mislocalisation and aggregation. Cell Stress Chaperones 2017; 22:893-902. [PMID: 28560609 PMCID: PMC5655364 DOI: 10.1007/s12192-017-0804-y] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2017] [Revised: 04/24/2017] [Accepted: 04/28/2017] [Indexed: 12/11/2022] Open
Abstract
ALS is characterised by a focal onset of motor neuron loss, followed by contiguous outward spreading of pathology throughout the nervous system, resulting in paralysis and death generally within a few years after diagnosis. The aberrant release and uptake of toxic proteins including SOD1 and TDP-43 and their subsequent propagation, accumulation and deposition in motor neurons may explain such a pattern of pathology. Previous work has suggested that the internalization of aggregates triggers stress granule formation. Given the close association of stress granules and TDP-43, we wondered whether internalisation of SOD1 aggregates stimulated TDP-43 cytosolic aggregate structures. Addition of recombinant mutant G93A SOD1 aggregates to NSC-34 cells was found to trigger a rapid shift of TDP-43 to the cytoplasm where it was still accumulated after 48 h. In addition, SOD1 aggregates also triggered cleavage of TDP-43 into fragments including a 25 kDa fragment. Collectively, this study suggests a role for protein aggregate uptake in TDP-43 pathology.
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Affiliation(s)
- Rafaa Zeineddine
- Illawarra Health and Medical Research Institute, Wollongong, NSW, Australia
- School of Biological Sciences, Science Medicine and Health Faculty, University of Wollongong, Wollongong, NSW, Australia
| | - Natalie E Farrawell
- Illawarra Health and Medical Research Institute, Wollongong, NSW, Australia
- School of Biological Sciences, Science Medicine and Health Faculty, University of Wollongong, Wollongong, NSW, Australia
| | - Isabella A Lambert-Smith
- Illawarra Health and Medical Research Institute, Wollongong, NSW, Australia
- School of Biological Sciences, Science Medicine and Health Faculty, University of Wollongong, Wollongong, NSW, Australia
| | - Justin J Yerbury
- Illawarra Health and Medical Research Institute, Wollongong, NSW, Australia.
- School of Biological Sciences, Science Medicine and Health Faculty, University of Wollongong, Wollongong, NSW, Australia.
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30
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Translating protein phosphatase research into treatments for neurodegenerative diseases. Biochem Soc Trans 2017; 45:101-112. [PMID: 28202663 DOI: 10.1042/bst20160157] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2016] [Revised: 11/21/2016] [Accepted: 11/23/2016] [Indexed: 12/11/2022]
Abstract
Many of the major neurodegenerative disorders are characterized by the accumulation of intracellular protein aggregates in neurons and other cells in brain, suggesting that errors in protein quality control mechanisms associated with the aging process play a critical role in the onset and progression of disease. The increased understanding of the unfolded protein response (UPR) signaling network and, more specifically, the structure and function of eIF2α phosphatases has enabled the development or discovery of small molecule inhibitors that show great promise in restoring protein homeostasis and ameliorating neuronal damage and death. While this review focuses attention on one or more eIF2α phosphatases, the wide range of UPR proteins that are currently being explored as potential drug targets bodes well for the successful future development of therapies to preserve neuronal function and treat neurodegenerative disease.
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31
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The Piezo1 protein ion channel functions in human nucleus pulposus cell apoptosis by regulating mitochondrial dysfunction and the endoplasmic reticulum stress signal pathway. Exp Cell Res 2017; 358:377-389. [PMID: 28705727 DOI: 10.1016/j.yexcr.2017.07.010] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2017] [Revised: 07/06/2017] [Accepted: 07/07/2017] [Indexed: 01/09/2023]
Abstract
The Piezo1 protein ion channel is a novel mechanical stretch-activated ion channel (SAC) closely related to mechanical signals. Mechanotransduction plays a crucial role in organ development and homeostasis. Previous studies identified Piezo1 and demonstrated that it is distinct from other ion channels with well-established roles in lower organisms. Mechanical stretch-activated ion channels from other organisms are not conserved in mammals or do not act as mechanically activated channels in mammals. In the current study, we explored the role of the Piezo1 ion channel in human nucleus pulposus cell (NP cell) apoptosis through mechanical force-induced mitochondrial dysfunction and endoplasmic reticulum stress. Reverse Transcription Polymerase chain reaction (RT-PCR), immunofluorescence, immunohistochemistry and Annexin V binding and propidium iodide analyses revealed that the Piezo1 protein ion channel was highly expressed in human NP cells, which are the primary cells that comprise the intervertebral disc. In patients with intervertebral disc degeneration (IVDD), the Piezo1 protein may play a crucial role in human NP cell apoptosis through mitochondrial dysfunction and endoplasmic reticulum stress under abnormal loading conditions. This study also verified that human NP cells have an intimate connection with the cytoskeleton upon treatment of the cells with the Piezo1 blocking peptide GsMTx4 from tarantula venom. In summary, Piezo1 functions in human NP cell apoptosis, which may be one underlying mechanism of apoptosis induced by abnormal loading in IVDD patients.
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32
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Bhinge A, Namboori SC, Zhang X, VanDongen AMJ, Stanton LW. Genetic Correction of SOD1 Mutant iPSCs Reveals ERK and JNK Activated AP1 as a Driver of Neurodegeneration in Amyotrophic Lateral Sclerosis. Stem Cell Reports 2017; 8:856-869. [PMID: 28366453 PMCID: PMC5390134 DOI: 10.1016/j.stemcr.2017.02.019] [Citation(s) in RCA: 91] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2016] [Revised: 02/21/2017] [Accepted: 02/23/2017] [Indexed: 12/14/2022] Open
Abstract
Although mutations in several genes with diverse functions have been known to cause amyotrophic lateral sclerosis (ALS), it is unknown to what extent causal mutations impinge on common pathways that drive motor neuron (MN)-specific neurodegeneration. In this study, we combined induced pluripotent stem cells-based disease modeling with genome engineering and deep RNA sequencing to identify pathways dysregulated by mutant SOD1 in human MNs. Gene expression profiling and pathway analysis followed by pharmacological screening identified activated ERK and JNK signaling as key drivers of neurodegeneration in mutant SOD1 MNs. The AP1 complex member JUN, an ERK/JNK downstream target, was observed to be highly expressed in MNs compared with non-MNs, providing a mechanistic insight into the specific degeneration of MNs. Importantly, investigations of mutant FUS MNs identified activated p38 and ERK, indicating that network perturbations induced by ALS-causing mutations converge partly on a few specific pathways that are drug responsive and provide immense therapeutic potential.
Genome correction of SOD1 E100G mutation corrects ALS phenotypes in MNs Activation of MAPK, AP1, WNT, cell-cycle, and p53 signaling in ALS MNs Pharmacological screening uncovers ERK and JNK signaling as therapeutic targets Susceptibility of MNs to degeneration may be due to heightened JUN activity in MNs
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Affiliation(s)
- Akshay Bhinge
- Stem Cell and Regenerative Biology, Genome Institute of Singapore, Singapore 138672, Singapore.
| | - Seema C Namboori
- Stem Cell and Regenerative Biology, Genome Institute of Singapore, Singapore 138672, Singapore
| | - Xiaoyu Zhang
- Program for Neuroscience and Behavioral Disorders, Duke-NUS Medical School, Singapore 169857, Singapore; NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore 119077, Singapore
| | - Antonius M J VanDongen
- Program for Neuroscience and Behavioral Disorders, Duke-NUS Medical School, Singapore 169857, Singapore
| | - Lawrence W Stanton
- Stem Cell and Regenerative Biology, Genome Institute of Singapore, Singapore 138672, Singapore; Department of Biological Sciences, National University of Singapore, Singapore 117543, Singapore.
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33
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Safiedeen Z, Rodríguez-Gómez I, Vergori L, Soleti R, Vaithilingam D, Douma I, Agouni A, Leiber D, Dubois S, Simard G, Zibara K, Andriantsitohaina R, Martínez MC. Temporal Cross Talk Between Endoplasmic Reticulum and Mitochondria Regulates Oxidative Stress and Mediates Microparticle-Induced Endothelial Dysfunction. Antioxid Redox Signal 2017; 26:15-27. [PMID: 27392575 DOI: 10.1089/ars.2016.6771] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
AIMS Circulating microparticles (MPs) from metabolic syndrome patients and those generated from apoptotic T cells induce endothelial dysfunction; however, the molecular and cellular mechanism(s) underlying in the effects of MPs remain to be elucidated. RESULTS Here, we show that both types of MPs increased expression of endoplasmic reticulum (ER) stress markers, X-box binding protein 1, p-eukaryotic translation initiation factor 2 α, and CHOP, and nuclear translocation of activating transcription factor 6 on human aortic endothelial cells (HAoECs). MPs decreased in vitro nitric oxide release by HAoECs, whereas in vivo MP injection into mice impaired the endothelium-dependent relaxation induced by acetylcholine. These effects were prevented when ER stress was inhibited, suggesting that ER stress is implicated in the endothelial effects induced by MPs. MPs affected mitochondrial function and evoked sequential increase of cytosolic and mitochondrial reactive oxygen species (ROS). Pharmacological inhibition of ER stress and silencing of neutral sphingomyelinase (SMase) with siRNA abrogated all MP-mediated effects. Neutralization of Fas ligand carried by MPs abolished effects induced by both MP types, whereas neutralization of low-density lipoprotein receptor on endothelial cells prevented T-lymphocyte MP-mediated effects. Innovation and Conclusion: Collectively, endothelial dysfunction triggered by MPs involves temporal cross talk between ER and mitochondria with respect to spatial regulation of ROS via the neutral SMase and interaction of MPs with Fas and/or low-density lipoprotein receptor. These results provide a novel molecular insight into the manner MPs mediate vascular dysfunction and allow identification of potential therapeutic targets to treat vascular complications associated with metabolic syndrome. Antioxid. Redox Signal. 26, 15-27.
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Affiliation(s)
- Zainab Safiedeen
- 1 INSERM U1063, Stress Oxydant et Pathologies Métaboliques, Institut de Biologie en Santé, Université d'Angers , Angers, France .,2 ER045, Laboratory of Stem Cells, PRASE, DSST, Lebanese University , Beirut, Lebanon
| | - Isabel Rodríguez-Gómez
- 1 INSERM U1063, Stress Oxydant et Pathologies Métaboliques, Institut de Biologie en Santé, Université d'Angers , Angers, France
| | - Luisa Vergori
- 1 INSERM U1063, Stress Oxydant et Pathologies Métaboliques, Institut de Biologie en Santé, Université d'Angers , Angers, France
| | - Raffaella Soleti
- 1 INSERM U1063, Stress Oxydant et Pathologies Métaboliques, Institut de Biologie en Santé, Université d'Angers , Angers, France
| | - Dayannath Vaithilingam
- 1 INSERM U1063, Stress Oxydant et Pathologies Métaboliques, Institut de Biologie en Santé, Université d'Angers , Angers, France
| | - Imene Douma
- 1 INSERM U1063, Stress Oxydant et Pathologies Métaboliques, Institut de Biologie en Santé, Université d'Angers , Angers, France
| | - Abdelali Agouni
- 3 Faculty of Health and Medical Sciences, University of Surrey , Guildford, United Kingdom
| | - Denis Leiber
- 1 INSERM U1063, Stress Oxydant et Pathologies Métaboliques, Institut de Biologie en Santé, Université d'Angers , Angers, France
| | - Séverine Dubois
- 1 INSERM U1063, Stress Oxydant et Pathologies Métaboliques, Institut de Biologie en Santé, Université d'Angers , Angers, France .,4 Centre Hospitalo-Universitaire d'Angers , Angers, France
| | - Gilles Simard
- 1 INSERM U1063, Stress Oxydant et Pathologies Métaboliques, Institut de Biologie en Santé, Université d'Angers , Angers, France .,4 Centre Hospitalo-Universitaire d'Angers , Angers, France
| | - Kazem Zibara
- 2 ER045, Laboratory of Stem Cells, PRASE, DSST, Lebanese University , Beirut, Lebanon .,5 Faculty of Sciences-I, Biology Department, Lebanese University , Beirut, Lebanon
| | - Ramaroson Andriantsitohaina
- 1 INSERM U1063, Stress Oxydant et Pathologies Métaboliques, Institut de Biologie en Santé, Université d'Angers , Angers, France .,4 Centre Hospitalo-Universitaire d'Angers , Angers, France
| | - M Carmen Martínez
- 1 INSERM U1063, Stress Oxydant et Pathologies Métaboliques, Institut de Biologie en Santé, Université d'Angers , Angers, France .,4 Centre Hospitalo-Universitaire d'Angers , Angers, France
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34
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Mathis S, Couratier P, Julian A, Vallat JM, Corcia P, Le Masson G. Management and therapeutic perspectives in amyotrophic lateral sclerosis. Expert Rev Neurother 2016; 17:263-276. [DOI: 10.1080/14737175.2016.1227705] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Affiliation(s)
- Stéphane Mathis
- Department of Neurology, Neuro-Muscular Unit and ALS Center, CHU de Bordeaux, groupe hospitalier Pellegrin, Bordeaux, France
| | - Philippe Couratier
- Department of Neurology, ALS center, Centre de compétence SLA-fédération Tours-Limoges, CHU de Limoges, Limoges, France
| | - Adrien Julian
- Department of Neurology, CHU Poitiers, University of Poitiers, Poitiers, France
| | - Jean-Michel Vallat
- Department and Laboratory of Neurology, Centre de Référence ‘neuropathies périphériques rares’, University Hospital of Limoges, Limoges, France
| | - Philippe Corcia
- Department of Neurology, ALS center, Centre de compétence SLA-fédération Tours-Limoges, CHU de Tours, Tours, France
| | - Gwendal Le Masson
- Department of Neurology, Neuro-Muscular Unit and ALS Center, CHU de Bordeaux, groupe hospitalier Pellegrin, Bordeaux, France
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35
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Grottelli S, Ferrari I, Pietrini G, Peirce MJ, Minelli A, Bellezza I. The Role of Cyclo(His-Pro) in Neurodegeneration. Int J Mol Sci 2016; 17:E1332. [PMID: 27529240 PMCID: PMC5000729 DOI: 10.3390/ijms17081332] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2016] [Revised: 08/04/2016] [Accepted: 08/08/2016] [Indexed: 02/06/2023] Open
Abstract
Neurodegenerative diseases may have distinct genetic etiologies and pathological manifestations, yet share common cellular mechanisms underpinning neuronal damage and dysfunction. These cellular mechanisms include excitotoxicity, calcium dysregulation, oxidative damage, ER stress and neuroinflammation. Recent data have identified a dual role in these events for glial cells, such as microglia and astrocytes, which are able both to induce and to protect against damage induced by diverse stresses. Cyclo(His-Pro), a cyclic dipeptide derived from the hydrolytic removal of the amino-terminal pyroglutamic acid residue of the hypothalamic thyrotropin-releasing hormone, may be important in regulating the nature of the glial cell contribution. Cyclo(His-Pro) is ubiquitous in the central nervous system and is a key substrate of organic cation transporters, which are strongly linked to neuroprotection. The cyclic dipeptide can also cross the brain-blood-barrier and, once in the brain, can affect diverse inflammatory and stress responses by modifying the Nrf2-NF-κB signaling axis. For these reasons, cyclo(His-Pro) has striking potential for therapeutic application by both parenteral and oral administration routes and may represent an important new tool in counteracting neuroinflammation-based degenerative pathologies. In this review, we discuss the chemistry and biology of cyclo(His-Pro), how it may interact with the biological mechanisms driving neurodegenerative disease, such as amyotrophic lateral sclerosis, and thereby act to preserve or restore neuronal function.
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Affiliation(s)
- Silvia Grottelli
- Dipartimento di Medicina Sperimentale, Università di Perugia, Polo Unico Sant'Andrea delle Fratte, Piazzale Gambuli, 06132 Perugia, Italy.
| | - Ilaria Ferrari
- Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano ed Istituto di Neuroscienze, Consiglio Nazionale delle Ricerche, Via Vanvitelli 32, 20129 Milano, Italy.
| | - Grazia Pietrini
- Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano ed Istituto di Neuroscienze, Consiglio Nazionale delle Ricerche, Via Vanvitelli 32, 20129 Milano, Italy.
| | - Matthew J Peirce
- Dipartimento di Medicina Sperimentale, Università di Perugia, Polo Unico Sant'Andrea delle Fratte, Piazzale Gambuli, 06132 Perugia, Italy.
| | - Alba Minelli
- Dipartimento di Medicina Sperimentale, Università di Perugia, Polo Unico Sant'Andrea delle Fratte, Piazzale Gambuli, 06132 Perugia, Italy.
| | - Ilaria Bellezza
- Dipartimento di Medicina Sperimentale, Università di Perugia, Polo Unico Sant'Andrea delle Fratte, Piazzale Gambuli, 06132 Perugia, Italy.
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Smith AST, Davis J, Lee G, Mack DL, Kim DH. Muscular dystrophy in a dish: engineered human skeletal muscle mimetics for disease modeling and drug discovery. Drug Discov Today 2016; 21:1387-1398. [PMID: 27109386 DOI: 10.1016/j.drudis.2016.04.013] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2016] [Revised: 03/24/2016] [Accepted: 04/15/2016] [Indexed: 01/16/2023]
Abstract
Engineered in vitro models using human cells, particularly patient-derived induced pluripotent stem cells (iPSCs), offer a potential solution to issues associated with the use of animals for studying disease pathology and drug efficacy. Given the prevalence of muscle diseases in human populations, an engineered tissue model of human skeletal muscle could provide a biologically accurate platform to study basic muscle physiology, disease progression, and drug efficacy and/or toxicity. Such platforms could be used as phenotypic drug screens to identify compounds capable of alleviating or reversing congenital myopathies, such as Duchene muscular dystrophy (DMD). Here, we review current skeletal muscle modeling technologies with a specific focus on efforts to generate biomimetic systems for investigating the pathophysiology of dystrophic muscle.
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Affiliation(s)
- Alec S T Smith
- Department of Bioengineering, University of Washington, Seattle, WA 98195, USA
| | - Jennifer Davis
- Department of Bioengineering, University of Washington, Seattle, WA 98195, USA; Department of Pathology, University of Washington, Seattle, WA 98195, USA; Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98109, USA; Center for Cardiovascular Biology, University of Washington, Seattle, WA 98109, USA
| | - Gabsang Lee
- Institute for Cell Engineering, Department of Neurology, The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - David L Mack
- Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98109, USA; Department of Rehabilitation Medicine, University of Washington, Seattle, WA 98195, USA
| | - Deok-Ho Kim
- Department of Bioengineering, University of Washington, Seattle, WA 98195, USA; Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98109, USA; Center for Cardiovascular Biology, University of Washington, Seattle, WA 98109, USA.
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Protein folding alterations in amyotrophic lateral sclerosis. Brain Res 2016; 1648:633-649. [PMID: 27064076 DOI: 10.1016/j.brainres.2016.04.010] [Citation(s) in RCA: 70] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2016] [Revised: 04/04/2016] [Accepted: 04/05/2016] [Indexed: 02/07/2023]
Abstract
Protein misfolding leads to the formation of aggregated proteins and protein inclusions, which are associated with synaptic loss and neuronal death in neurodegenerative diseases. Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that targets motor neurons in the brain, brainstem and spinal cord. Several proteins misfold and are associated either genetically or pathologically in ALS, including superoxide dismutase 1 (SOD1), Tar DNA binding protein-43 (TDP-43), Ubiquilin-2, p62, VCP, and dipeptide repeat proteins produced by unconventional repeat associated non-ATG translation of the repeat expansion in C9ORF72. Chaperone proteins, including heat shock proteins (Hsp׳s) and the protein disulphide isomerase (PDI) family, assist in protein folding and therefore can prevent protein misfolding, and have been implicated as being protective in ALS. In this review we provide an overview of the current literature regarding the molecular mechanisms of protein misfolding and aggregation in ALS, and the role of chaperones as potential targets for therapeutic intervention. This article is part of a Special Issue entitled SI:ER stress.
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