The DOI matches its Crossref record; 9 of the 9 references it cites were found in a registry or an index.
Ubiquitination of -synuclein by Siah-1 promotes -synuclein aggregation and apoptotic cell death
Open accessAbstract
Point mutations and gene multiplication of alpha-synuclein cause autosomal dominant familial Parkinson's disease (PD). Moreover, alpha-synuclein- and ubiquitin-positive inclusion bodies are the pathological hallmarks of PD and several other neurodegenerative diseases, such as dementia with Lewy bodies and multiple system atrophy. Despite the presence of ubiquitinated alpha-synuclein species in Lewy bodies, the regulation of alpha-synuclein ubiquitination and its role in Lewy body formation and neurodegeneration remain poorly understood. Here, we report that alpha-synuclein interacts and colocalizes with mammalian seven in absentia homologue-1 (Siah-1), a RING-type E3 ubiquitin-protein ligase. Siah-1 binds the brain-enriched E2 ubiquitin-conjugating enzyme UbcH8 and facilitates mono- and di-ubiquitination of alpha-synuclein in vivo. The ubiquitination of alpha-synuclein by Siah-1 is disrupted by the PD-linked A30P mutation but not by A53T mutation. We find that Siah-1-mediated ubiquitination does not target alpha-synuclein for degradation by the proteasome, but rather, it promotes alpha-synuclein aggregation and enhances alpha-synuclein toxicity. Our findings suggest that Siah-1-mediated alpha-synuclein ubiquitination may play a critical role in Lewy body formation and PD pathogenesis.
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AlaSOPro mutation in the gene encoding α-synuclein in Parkinson's disease
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α-synuclein locus duplication as a cause of familial Parkinson's disease
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α-Synuclein Is Degraded by Both Autophagy and the Proteasome
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PINK1 Protects against Oxidative Stress by Phosphorylating Mitochondrial Chaperone TRAP1
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Self-citationPhosphorylated α-Synuclein Is Ubiquitinated in α-Synucleinopathy Lesions
Hasegawa, M., Fujiwara, H., Nonaka, T., Wakabayashi, K., Takahashi, H., Lee, V. M.-Y., Trojanowski, J. Q., Mann, D., & Iwatsubo, T. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m208046200 · Cited by 428
A binding motif for Siah ubiquitin ligase
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Degradation of misfolded proteins in neurodegenerative diseases: Therapeutic targets and strategies
Ciechanover, A., & Kwon, Y. T. (2015) · Experimental & Molecular Medicine · doi:10.1038/emm.2014.117 · Cited by 898
Cell Biology and Pathophysiology of α-Synuclein
Burré, J., Sharma, M., & Südhof, T. C. (2018) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a024091 · Cited by 579
Zhong, Q., Xiao, X., Qiu, Y., Xu, Z., Chen, C., Chong, B., Zhao, X., Hai, S., Li, S., An, Z., et al. (2023) · MedComm · doi:10.1002/mco2.261 · Cited by 442
Oueslati, A., Fournier, M., & Lashuel, H. A. (2010) · Progress in Brain Research · doi:10.1016/s0079-6123(10)83007-9 · Cited by 347
The multiple levels of regulation by p53 ubiquitination
Lee, J. T., & Gu, W. (2010) · Cell Death & Differentiation · doi:10.1038/cdd.2009.77 · Cited by 289
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Metadata
- Authors
- Lee, J. T., Wheeler, T. C., Li, L., & Chin, L.-S.
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2007-11-27
- Volume
- 17
- Issue
- 6
- Pages
- 906-917
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- OpenAlex
- W2106318486
- Cited by
- 170
- References
- 9
- FWCI
- 6.14
- Type
- journal article
- Language
- en
- Open access
- bronze
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- Lee, J. T., Wheeler, T. C., Li, L., & Chin, L.-S. (2007). Ubiquitination of -synuclein by Siah-1 promotes -synuclein aggregation and apoptotic cell death. Human Molecular Genetics. https://doi.org/10.1093/hmg/ddm363
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