Extracellular α-synuclein enters dopaminergic cells by modulating flotillin-1–assisted dopamine transporter endocytosis

Junpei Kobayashi, Takafumi Hasegawa, Naoto Sugeno, Shun Yoshida, Tetsuya Akiyama, Koki Fujimori, Hiroyasu Hatakeyama, Yasuo Miki, Arata Tomiyama, Yasushi Kawata, Mitsunori Fukuda, Ichiro Kawahata, Tohru Yamakuni, Michinori Ezura, Akio Kikuchi, Toru Baba, Atsushi Takeda, Makoto Kanzaki, Koichi Wakabayashi, Hideyuki OkanoMasashi Aoki

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

The neuropathological hallmarks of Parkinson's disease (PD) include the appearance of α-synuclein (α-SYN)-positive Lewy bodies (LBs) and the loss of catecholaminergic neurons. Thus, a potential mechanism promoting the uptake of extracellular α-SYN may exist in susceptible neurons. Of the various differentially expressed proteins, we are interested in flotillin (FLOT)-1 because this protein is highly expressed in the brainstem catecholaminergic neurons and is strikingly up-regulated in PD brains. In this study, we found that extracellular monomeric and fibrillar α-SYN can potentiate FLOT1–dopamine transporter (DAT) binding and pre-endocytic clustering of DAT on the cell surface, thereby facilitating DAT endocytosis and down-regulating its transporter activity. Moreover, we demonstrated that α-SYN itself exploited the DAT endocytic process to enter dopaminergic neuron-like cells, and both FLOT1 and DAT were found to be the components of LBs. Altogether, these findings revealed a novel role of extracellular α-SYN on cellular trafficking of DAT and may provide a rationale for the cell type-specific, functional, and pathologic alterations in PD.—Kobayashi, J., Hasegawa, T., Sugeno, N., Yoshida, S., Akiyama, T., Fujimori, K., Hatakeyama, H., Miki, Y., Tomiyama, A., Kawata, Y., Fukuda, M., Kawahata, I., Yamakuni, T., Ezura, M., Kikuchi, A., Baba, T., Takeda, A., Kanzaki, M., Wakabayashi, K., Okano, H., Aoki, M. Extracellular α-synuclein enters dopaminergic cells by modulating flotillin-1–assisted dopamine transporter endocytosis. FASEB J. 33, 10240–10256 (2019). www.fasebj.org.

Original languageEnglish
Pages (from-to)10240-10256
Number of pages17
JournalFASEB Journal
Volume33
Issue number9
DOIs
Publication statusPublished - 2019 Sep 1

Keywords

  • DAT
  • Lewy body
  • Parkinson's disease
  • endocytosis
  • endosome

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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  • Cite this

    Kobayashi, J., Hasegawa, T., Sugeno, N., Yoshida, S., Akiyama, T., Fujimori, K., Hatakeyama, H., Miki, Y., Tomiyama, A., Kawata, Y., Fukuda, M., Kawahata, I., Yamakuni, T., Ezura, M., Kikuchi, A., Baba, T., Takeda, A., Kanzaki, M., Wakabayashi, K., ... Aoki, M. (2019). Extracellular α-synuclein enters dopaminergic cells by modulating flotillin-1–assisted dopamine transporter endocytosis. FASEB Journal, 33(9), 10240-10256. https://doi.org/10.1096/fj.201802051R