Phosphorylated α-Synuclein Is Ubiquitinated in α-Synucleinopathy Lesions
Open accessAbstract
alpha-Synuclein is one of the major components of intracellular fibrillary aggregates in the brains of a subset of neurodegenerative disorders, including Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, and Hallervorden-Spatz disease, which are referred to as alpha-synucleinopathies. We have shown previously (Fujiwara, H., Hasegawa, M., Dohmae, N., Kawashima, A., Masliah, E., Goldberg, M. S., Shen, J., Takio, K., and Iwatsubo, T. (2002) Nat. Cell Biol. 4, 160-164) that alpha-synuclein deposited in synucleinopathy brains is extensively phosphorylated at Ser-129 and migrates at 15 kDa. Here we examined the biochemical characteristics of the additional, higher molecular mass species of phosphorylated alpha-synuclein-positive polypeptides that also are recovered in the Sarkosyl-insoluble fraction of synucleinopathy and migrate at about 22 and 29 kDa. These 22 and 29 kDa bands were positive for three different anti-ubiquitin antibodies and comigrated perfectly with in vitro ubiquitinated alpha-synuclein that may correspond to mono- and diubiquitinated alpha-synuclein, respectively. Furthermore, cyanogen bromide cleavage of the 22 and 29 kDa polypeptides shifted the mobility to 19 and 26 kDa, respectively, and they retained immunoreactivity for both ubiquitin and alpha-synuclein. Finally, protein sequence analysis showed that the 19 kDa band contained two amino-terminal sequences of alpha-synuclein and ubiquitin. These results strongly suggest that phosphorylated alpha-synuclein is targeted to mono- and diubiquitination in synucleinopathy brains, which may have implications for mechanisms of these diseases.
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α-Synuclein is degraded by proteasomes, and phosphorylated α-synuclein is ubiquitinated in α-synucleinopathy lesions, indicating that the ubiquitin-proteasome system degrades phosphorylated synuclein.
“α-Synuclein is degraded by proteasomes [106,107], and phosphorylated α-synuclein is ubiquitinated in α-synucleinopathy lesions [108], indicating that the ubiquitin-proteasome system degrades phosphorylated synuclein.”
From Degradation of Tyrosine Hydroxylase by the Ubiquitin-Proteasome System in the Pathogenesis of Parkinson’s Disease and Dopa-Responsive Dystonia (2020) · cites this paper as [108]
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- Authors
- Hasegawa, M., Fujiwara, H., Nonaka, T., Wakabayashi, K., Takahashi, H., Lee, V. M.-Y., Trojanowski, J. Q., Mann, D., & Iwatsubo, T.
- Affiliations
- Tokyo Institute of Psychiatry (JP)
- The University of Tokyo (JP)
- Hirosaki University (JP)
- Brain Research Institute, Niigata University (JP)
- University of Pennsylvania (US)
- Salford Royal Hospital (GB)
- Corresponding author
- Hasegawa, Masato
- ORCID
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2002-12
- Volume
- 277
- Issue
- 50
- Pages
- 49071-49076
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W1487645896
- Cited by
- 428
- References
- 35
- Citations by year
- 2026: 8 · 2025: 14 · 2024: 18 · 2023: 15 · 2022: 20 · 2021: 32 · 2020: 20 · 2019: 26 · 2018: 24 · 2017: 21 · 2016: 20 · 2015: 14 · 2014: 11 · 2013: 14 · 2012: 13
- FWCI
- 12.39
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Alzheimer's Association
- National Institutes of Health
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Keywords
- alpha-synuclein, phosphorylation, ubiquitination, synucleinopathies, Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, Hallervorden-Spatz disease, monoubiquitination, neurodegeneration
- MeSH terms
- Aged, Amino Acid Sequence, Brain, Cyanogen Bromide, Female, Humans, Male, Molecular Sequence Data, Nerve Tissue Proteins, Phosphorylation, Neurodegenerative Diseases, Ubiquitin, Synucleins, alpha-Synuclein
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