Cited by 428Parkinson's Disease Mechanisms and TreatmentsAlzheimer's disease research and treatmentsUbiquitin and proteasome pathways

Phosphorylated α-Synuclein Is Ubiquitinated in α-Synucleinopathy Lesions

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Hasegawa, Masato, Fujiwara, Hideo, Nonaka, Takashi, Wakabayashi, Koichi, Takahashi, Hitoshi, Lee, Virginia M.-Y., Trojanowski, John Q., Mann, David +1 more·2002·Journal of Biological Chemistry

Abstract

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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  1. Spillantini, M. G., Crowther, R. A., Jakes, R., Hasegawa, M., and Goedert, M. (1998) Proc. Natl. Acad. Sci. U. S. A. 95, 6469 -6473
  2. Shaw, G., and Chau, V. (1988) Proc. Natl. Acad. Sci. U. S. A. 85, 2854 -2858

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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
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
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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