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J. Biol. Chem., Vol. 277, Issue 50, 49071-49076, December 13, 2002
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From the
Phosphorylated
-Synuclein Is Ubiquitinated in
-Synucleinopathy Lesions*
§¶,,
,,, Department of Molecular Neurobiology, Tokyo
Institute of Psychiatry, Tokyo Metropolitan Organization for Medical
Research, 2-1-8 Kamikitazawa, Setagaya-ku, Tokyo 156-8585, Japan, the
§ Department of Neuropathology and Neuroscience, Graduate
School of Pharmaceutical Science, The University of Tokyo, 7-3-1 Hongo,
Bunkyo-ku, Tokyo 113-0033, Japan, the Department of
Neuropathology, Hirosaki University School of Medicine, 5 Zaifu-cho,
Hirosaki, 036-8562, Japan, the ** Department of
Pathology, Brain Research Institute, Niigata University, 1 Asahimachi,
Niigata 951-8585, Japan; Department of
Pathology and Laboratory Medicine, University of Pennsylvania School of
Medicine, Philadelphia, Pennsylvania 19104-4283, and the
§§ Greater Manchester Neurosciences Centre, Hope
Hospital, Stott Lane, Salford M6 8HD, United Kingdom
-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
-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 -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 -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 -synuclein that may
correspond to mono- and diubiquitinated -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 -synuclein.
Finally, protein sequence analysis showed that the 19 kDa band
contained two amino-terminal sequences of -synuclein and ubiquitin.
These results strongly suggest that phosphorylated -synuclein is
targeted to mono- and diubiquitination in synucleinopathy brains, which
may have implications for mechanisms of these diseases.
*
This work was supported by a Grant-in-Aid for Scientific
Research on Priority Area C, Advanced Brain Science Project from the
Ministry of Education, Culture, Sports, Science, and Technology, Japan
(to M. H. and T. I.) and grants from the National Institutes of
Health and the Alzheimer's Association (to V. M.-Y. L. and J. Q. T.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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