The pathogenic mechanisms of polyglutamine diseases and current therapeutic strategies
Open accessAbstract
Expansion of CAG trinucleotide repeat within the coding region of several genes results in the production of proteins with expanded polyglutamine (PolyQ) stretch. The expression of these pathogenic proteins leads to PolyQ diseases, such as Huntington's disease or several types of spinocerebellar ataxias. This family of neurodegenerative disorders is characterized by constant progression of the symptoms and molecularly, by the accumulation of mutant proteins inside neurons causing their dysfunction and eventually death. So far, no effective therapy actually preventing the physical and/or mental decline has been developed. Experimental therapeutic strategies either target the levels or processing of mutant proteins in an attempt to prevent cellular deterioration, or they are aimed at the downstream pathologic effects to reverse or ameliorate the caused damages. Certain pathomechanistic aspects of PolyQ disorders are discussed here. Relevance of disease models and recent knowledge of therapeutic possibilities is reviewed and updated.
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Phosphorylation of polyglutamine disease proteins plays important roles in disease pathogenesis by affecting proteolytic cleavage, toxic conformational change, nuclear transport, and gene transcription.
“In neurodegenerative diseases, phosphorylation of polyglutamine disease proteins plays important roles in disease pathogenesis by affecting diverse aspects of pathogenicity including proteolytic cleavage, induction of a toxic conformational change, nuclear transport, and gene transcription (Bauer and Nukina, 2009; Pennuto et al., 2009).”
From Polyglutamine Disease Toxicity Is Regulated by Nemo-like Kinase in Spinocerebellar Ataxia Type 1 (2013) · cites this paper as Bauer and Nukina, 2009
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30 years of repeat expansion disorders: What have we learned and what are the remaining challenges?
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Self-citationPolyglutamine Disease Toxicity Is Regulated by Nemo-like Kinase in Spinocerebellar Ataxia Type 1
Ju, H., Kokubu, H., Todd, T. W., Kahle, J. J., Kim, S., Richman, R., Chirala, K., Orr, H. T., Zoghbi, H. Y., & Lim, J. (2013) · The Journal of Neuroscience · doi:10.1523/jneurosci.3465-12.2013 · Cited by 31 · see citing works
“…of polyglutamine disease proteins plays important roles in disease pathogenesis by affecting diverse aspects of pathogenicity, including proteolytic cleavage, induction of a toxic conformational change, nuclear transport, and gene transcription (Bauer and Nukina, 2009; Pennuto et al., 2009).”
Background
- Authors
- Bauer, P. O., & Nukina, N.
- Affiliations
- RIKEN (JP)
- RIKEN Center for Brain Science (JP)
- Venue
- Journal of Neurochemistry
- Publisher
- Wiley
- Published
- 2009-09
- Volume
- 110
- Issue
- 6
- Pages
- 1737-1765
- ISSN
- 0022-3042 (ISSN-L)
- 1471-4159
- OpenAlex
- W2008675515
- Cited by
- 178
- References
- 10
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 6 · 2023: 2 · 2022: 3 · 2021: 3 · 2020: 4 · 2019: 2 · 2018: 8 · 2017: 3 · 2016: 15 · 2015: 16 · 2014: 15 · 2013: 21 · 2012: 22
- FWCI
- 2.13
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Neurochemistry (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Keywords
- polyglutamine diseases, CAG repeat expansion, Huntington's disease, spinocerebellar ataxia, neurodegeneration, pathophysiological mechanisms, treatment options, disease models
- MeSH terms
- Animals, Disease Models, Animal, Humans, Mutation, Nerve Tissue Proteins, Peptides, Protein Folding, Neurodegenerative Diseases, Trinucleotide Repeat Expansion
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