Failure of protein quality control in amyotrophic lateral sclerosis
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The protein chaperoning and ubiquitin-proteasome systems perform many homeostatic functions within cells involving protein folding, transport and degradation. Of paramount importance is ridding cells of mutant or post-translationally modified proteins that otherwise tend to aggregate into insoluble complexes and form inclusions. Such inclusions are characteristic of many neurodegenerative diseases and implicate protein misfolding and aggregation as common aspects of pathogenesis. In the most common familial form of ALS, mutations in SOD1 promote misfolding of the protein and target it for degradation by proteasomes. Although proteasomes can degrade the mutant proteins efficiently, altered solubility and aggregation of mutant SOD1 are features of the disease and occur most prominently in the most vulnerable cells and tissues. Indeed, lumbar spinal cord of mutant SOD1 transgenic mice show early reduction in their capacity for protein chaperoning and proteasome-mediated hydrolysis of substrates, and motor neurons are particularly vulnerable to aggregation of mutant SOD1. A high threshold for upregulating key pathways in response to the stress of added substrate load may contribute to this vulnerability. The broad spectrum neuroprotective capability and efficacy of some chaperone-based therapies in preclinical models makes these pathways attractive as targets for therapy in ALS, as well as other neurodegenerative diseases. A better understanding of the mechanisms governing the regulation of protein chaperones and UPS components would facilitate development of treatments that upregulate these pathways in a coordinated manner in neural tissue without long term toxicity.
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In neurological disease and aging, modified proteins are the histopathological hallmarks of a number of diseases, such as SOD1 in amyotrophic lateral sclerosis (ALS), and a class of diseases long referred to as the proteinopathies, including tauopathies in Alzheimer's disease and inclusions of amyloid beta, alpha-synuclein in Parkinson's and multiple secondary ubiquitinopathies.
“In neurological disease and aging, modified proteins are the histopathological hallmarks of a number of diseases, such as SOD1 in amyotrophic lateral sclerosis (ALS) 56,57 , and a class of diseases long referred to as the proteinopathies 57 , including tauopathies in Alzheimer's disease 58 and inclusions of amyloidβ 59 , α -synuclein in Parkinson's 60,61 and multiple secondary ubiquitinopathies”
From How many human proteoforms are there? (2018) · cites this paper as [63]
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- Authors
- Kabashi, E., & Durham, H. D.
- Affiliations
- Montreal Neurological Institute and Hospital (CA)
- Venue
- Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease
- Publisher
- Elsevier BV
- Published
- 2006-11
- Volume
- 1762
- Issue
- 11-12
- Pages
- 1038-1050
- ISSN
- 0925-4439 (ISSN-L)
- OpenAlex
- W2117212431
- Cited by
- 90
- References
- 151
- Citations by year
- 2026: 1 · 2024: 1 · 2023: 1 · 2022: 1 · 2021: 4 · 2020: 3 · 2019: 3 · 2018: 6 · 2017: 6 · 2016: 6 · 2015: 2 · 2014: 3 · 2013: 5 · 2012: 7
- FWCI
- 1.36
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Keywords
- amyotrophic lateral sclerosis, protein quality control, molecular chaperones, ubiquitin-proteasome system, SOD1 mutations, protein misfolding, protein aggregation, motor neurons, proteasomal degradation, transgenic mouse model
- MeSH terms
- Superoxide Dismutase-1, Amyotrophic Lateral Sclerosis, Animals, Humans, Lumbar Vertebrae, Mice, Transgenic, Models, Biological, Neurons, Superoxide Dismutase, Signal Transduction, Protein Folding, Oxidative Stress, Molecular Chaperones, Ubiquitin, Proteasome Endopeptidase Complex, Mice
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