Over-expression of inducible HSP70 chaperone suppresses neuropathology and improves motor function in SCA1 mice
Abstract
Many neurodegenerative diseases are caused by gain-of-function mechanisms in which the disease-causing protein is altered, becomes toxic to the cell, and aggregates. Among these 'proteinopathies' are Alzheimer's and Parkinson's disease, prion disorders and polyglutamine diseases. Members of this latter group, also known as triplet repeat diseases, are caused by the expansion of unstable CAG repeats coding for glutamine within the respective proteins. Spinocerebellar ataxia type 1 (SCA1) is one such disease, characterized by loss of motor coordination due to the degeneration of cerebellar Purkinje cells and brain stem neurons. In SCA1 and several other polyglutamine diseases, the expanded protein aggregates into nuclear inclusions (NIs). Because these NIs accumulate molecular chaperones, ubiquitin and proteasomal subunits--all components of the cellular protein re-folding and degradation machinery--we hypothesized that protein misfolding and impaired protein clearance might underlie the pathogenesis of polyglutamine diseases. Over-expressing specific chaperones reduces protein aggregation in transfected cells and suppresses neurodegeneration in invertebrate animal models of polyglutamine disorders. To determine whether enhancing chaperone activity could mitigate the phenotype in a mammalian model, we crossbred SCA1 mice with mice over-expressing a molecular chaperone (inducible HSP70 or iHSP70). We found that high levels of HSP70 did indeed afford protection against neurodegeneration.
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Overexpression of heat shock protein 70 protects against age- and disease-related tissue degeneration in brain, heart, and skeletal muscle.
“Overexpression of heat shock protein 70 (HSP70), a chaperone protein that recognizes damaged proteins in CMA, also protects against age- and disease-related tissue degeneration in brain, heart and skeletal muscle90–92.”
From Stem cell aging: mechanisms, regulators and therapeutic opportunities (2014) · cites this paper as [90]
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- Authors
- Cummings, C. J.
- Affiliations
- Baylor College of Medicine (US)
- Corresponding author
- Cummings, C. J.
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2001-07-01
- Volume
- 10
- Issue
- 14
- Pages
- 1511-1518
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- OpenAlex
- W2145669564
- Cited by
- 485
- References
- 25
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 5 · 2023: 3 · 2022: 6 · 2021: 3 · 2020: 11 · 2019: 11 · 2018: 11 · 2017: 10 · 2016: 15 · 2015: 8 · 2014: 24 · 2013: 25 · 2012: 20
- FWCI
- 14.24
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Human Molecular Genetics (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Neurological Disorders and Stroke (NS 27699)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Keywords
- spinocerebellar ataxia type 1, HSP70, polyglutamine diseases, triplet repeat diseases, protein aggregation, intranuclear inclusions, neurodegeneration, Purkinje cells, motor function, protein misfolding, protein clearance, transgenic mice
- MeSH terms
- Ataxins, Ataxin-1, Animals, Brain Stem, Inclusion Bodies, Cerebellum, Mice, Transgenic, Motor Activity, Nerve Tissue Proteins, Neurons, Nuclear Proteins, Protein Conformation, Purkinje Cells, Gene Expression, Protein Structure, Tertiary, HSP70 Heat-Shock Proteins, Trinucleotide Repeats, Neurodegenerative Diseases, Mice, In Vitro Techniques
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