Post-translational modifications of expanded polyglutamine proteins: impact on neurotoxicity
Open accessAbstract
Polyglutamine diseases are a family of nine neurodegenerative disorders caused by expansion in different genes of a CAG triplet repeat stretch, which encodes an elongated polyglutamine tract. This polyglutamine tract is thought to confer a toxic gain of function to the bearing proteins, which leads to late onset and progressive loss of neurons in specific regions of the central nervous system. The mechanisms underlying specificity for neuronal vulnerability remain enigmatic. One explanation is that the polyglutamine tract is not the only determinant of neurodegeneration and that protein context and post-translational events may also be crucial for pathogenesis. Here, we review how post-translational modifications of the polyglutamine proteins contribute to modulate neurotoxicity.
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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 Pennuto et al., 2009
The Interplay Between Post-translational Modifications section (page not provided) says phosphorylation affects proteolytic cleavage of polyQ proteins, and the Phosphorylation section reports effects on their aggregation and toxicity. It does not establish induction of a toxic conformational change. Its examples of phosphorylation affecting nuclear transport and transcription concern androgen receptor in prostate cancer cells; the paper says it is unknown whether those phosphorylation sites affect polyQ androgen-receptor toxicity. (LLM, conf=0.86)
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Cites
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Ochaba, J., Monteys, A. M., O’Rourke, J. G., Reidling, J. C., Steffan, J. S., Davidson, B. L., & Thompson, L. M. (2016) · Neuron · doi:10.1016/j.neuron.2016.03.016 · Cited by 94 · see citing works
Polyglutamine 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
- Pennuto, M., Palazzolo, I., & Poletti, A.
- Affiliations
- University of Pennsylvania (US)
- National Institutes of Health (US)
- University of Milan (IT)
- Corresponding author
- Pennuto, M.
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2009-04-15
- Volume
- 18
- Issue
- R1
- Pages
- R40-R47
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- OpenAlex
- W2158110928
- Cited by
- 82
- References
- 5
- Citations by year
- 2024: 2 · 2023: 2 · 2022: 1 · 2021: 1 · 2020: 5 · 2019: 6 · 2018: 1 · 2017: 5 · 2016: 8 · 2015: 9 · 2014: 8 · 2013: 7 · 2012: 6
- FWCI
- 0.78
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Human Molecular Genetics (publishedVersion)
- PubMed (publishedVersion)
- Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, other-oa)
- Institutional Research Information System (Università degli Studi di Trento) (submittedVersion)
- Padua Research Archive (University of Padova) (submittedVersion)
- 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 › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Keywords
- polyglutamine diseases, post-translational modification, neurotoxicity, CAG repeat expansion, gain-of-function, neuronal vulnerability, neurodegeneration
- MeSH terms
- Animals, Humans, Nerve Tissue Proteins, Peptides, Protein Processing, Post-Translational, Neurodegenerative Diseases
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