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α-Synuclein is phosphorylated in synucleinopathy lesions

Nature Cell Biology volume 4, pages 160–164 (2002)Cite this article

Abstract

The deposition of the abundant presynaptic brain protein α-synuclein as fibrillary aggregates in neurons or glial cells is a hallmark lesion in a subset of neurodegenerative disorders. These disorders include Parkinson's disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy, collectively referred to as synucleinopathies1,2. Importantly, the identification of missense mutations in the α-synuclein gene in some pedigrees of familial PD has strongly implicated α-synuclein in the pathogenesis of PD and other synucleinopathies3. However, specific post-translational modifications that underlie the aggregation of α-synuclein in affected brains have not, as yet, been identified. Here, we show by mass spectrometry analysis and studies with an antibody that specifically recognizes phospho-Ser 129 of α-synuclein, that this residue is selectively and extensively phosphorylated in synucleinopathy lesions. Furthermore, phosphorylation of α-synuclein at Ser 129 promoted fibril formation in vitro. These results highlight the importance of phosphorylation of filamentous proteins in the pathogenesis of neurodegenerative disorders.

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Figure 1: Purification and characterization of α-synuclein from human brains.
Figure 2: Identification of a phosphorylated amino acid residue by nanoelectrospray tandem mass spectrometry.
Figure 3: Characterization of the anti-PSer129 antibody.
Figure 4: Immunohistochemistry of synucleinopathy lesions.
Figure 5: Phosphorylation of Ser 129 of recombinant human α-synuclein and its effect on fibrillization.

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Acknowledgements

We thank P.T. Lansbury Jr. and J.-C. Rochet for advice on oligomer formation experiments, J.Q. Trojanowski, V.M.-Y. Lee and D.W. Dickson for frozen DLB samples, D.M.A. Mann for helpful comments on the manuscript and brain samples, M. Goedert for an expression plasmid encoding recombinant α-synuclein, Y. Ihara and T. Katada for making the TOF/MS and fluorospectrometer available, respectively, H. Nishina and D. Kitagawa for advice on in vitro phosphorylation experiments, T. Hashimoto for assistance in thioflavin-T and oligomer assays, M. Baba and T. Kuwahara for technical assistance, and A. Koyama, H. Miake and M. Takahashi for helpful discussions. This work was supported by grants-in-aid from the Ministry of Health and Welfare and the Ministry of Education, Science, Culture and Sports, Japan.

Author information

Author notes

  1. Masato Hasegawa

    Present address: Department of Molecular Neurobiology, Tokyo Institute of Psychiatry, Tokyo, 156-8585, Japan

  2. Hideo Fujiwara and Masato Hasegawa: These authors contributed equally to the work.

  3. Masato Hasegawa and Takeshi Iwatsubo: These contributors both served as senior authors.

Authors and Affiliations

  1. Department of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, 113-0033, Tokyo, Japan

    Hideo Fujiwara, Masato Hasegawa, Akiko Kawashima & Takeshi Iwatsubo

  2. Biomolecular Characterization Division, Characterization Center, RIKEN, Wako, 351-0198, Saitama, Japan

    Naoshi Dohmae & Koji Takio

  3. Department of Neurosciences, University of California San Diego, La Jolla, 92093-0624, CA, USA

    Eliezer Masliah

  4. Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, 02115, MA, USA

    Matthew S. Goldberg & Jie Shen

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  1. Hideo Fujiwara
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Corresponding author

Correspondence to Takeshi Iwatsubo.

Supplementary information

Supplementary figure

Figure S1 Quantitative analysis of the extent of α-synuclein phosphorylation in the urea-soluble fractions of DLB brains. (PDF 600 kb)

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Fujiwara, H., Hasegawa, M., Dohmae, N. et al. α-Synuclein is phosphorylated in synucleinopathy lesions. Nat Cell Biol 4, 160–164 (2002). https://doi.org/10.1038/ncb748

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