The DOI matches its Crossref record; 60 of the 60 references it cites were found in a registry or an index.
α-synuclein acts in the nucleus to inhibit histone acetylation and promote neurotoxicity
Abstract
Alpha-synuclein is a neuronal protein implicated genetically in Parkinson's disease. alpha-synuclein localizes to the nucleus and presynaptic nerve terminals. Here we show that alpha-synuclein mediates neurotoxicity in the nucleus. Targeting of alpha-synuclein to the nucleus promotes toxicity, whereas cytoplasmic sequestration is protective in both cell culture and transgenic Drosophila. Toxicity of alpha-synuclein can be rescued by administration of histone deacetylase inhibitors in both cell culture and transgenic flies. Alpha-synuclein binds directly to histones, reduces the level of acetylated histone H3 in cultured cells and inhibits acetylation in histone acetyltransferase assays. Alpha-synuclein mutations that cause familial Parkinson's disease, A30P and A53T, exhibit increased nuclear targeting in cell culture. These findings implicate nuclear alpha-synuclein in promoting nigrostriatal degeneration in Parkinson's disease and encourage exploration of histone deacetylase inhibitors as potential therapies for the disorder.
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Cites
Mutation in the α-Synuclein Gene Identified in Families with Parkinson's Disease
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α-Synuclein Locus Triplication Causes Parkinson's Disease
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AlaSOPro mutation in the gene encoding α-synuclein in Parkinson's disease
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The new mutation, E46K, of α‐synuclein causes parkinson and Lewy body dementia
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A Drosophila model of Parkinson's disease
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Self-citationα-synuclein locus duplication as a cause of familial Parkinson's disease
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Mice Lacking α-Synuclein Display Functional Deficits in the Nigrostriatal Dopamine System
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Synuclein: a neuron-specific protein localized to the nucleus and presynaptic nerve terminal
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Cited by
-Synuclein in Parkinson's Disease
Stefanis, L. (2012) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a009399 · Cited by 1,446
α-synuclein toxicity in neurodegeneration: mechanism and therapeutic strategies
Wong, Y. C., & Krainc, D. (2017) · Nature Medicine · doi:10.1038/nm.4269 · Cited by 897
Bendor, J. T., Logan, T. P., & Edwards, R. H. (2013) · Neuron · doi:10.1016/j.neuron.2013.09.004 · Cited by 825
Multiple roles of HDAC inhibition in neurodegenerative conditions
Chuang, D.-M., Leng, Y., Marinova, Z., Kim, H.-J., & Chiu, C.-T. (2009) · Trends in Neurosciences · doi:10.1016/j.tins.2009.06.002 · Cited by 676
Schulz-Schaeffer, W. J. (2010) · Acta Neuropathologica · doi:10.1007/s00401-010-0711-0 · Cited by 627
Metadata
- Authors
- Kontopoulos, E., Parvin, J. D., & Feany, M. B.
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2006-09-07
- Volume
- 15
- Issue
- 20
- Pages
- 3012-3023
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- OpenAlex
- W2167678675
- Cited by
- 537
- References
- 60
- FWCI
- 12.76
- Type
- journal article
- Language
- en
- Open access
- closed
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- Kontopoulos, E., Parvin, J. D., & Feany, M. B. (2006). α-synuclein acts in the nucleus to inhibit histone acetylation and promote neurotoxicity. Human Molecular Genetics. https://doi.org/10.1093/hmg/ddl243
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