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Extracellular α‐synuclein enters dopaminergic cells by modulating flotillin‐1–assisted dopamine transporter endocytosis
Author(s) -
Kobayashi Junpei,
Hasegawa Takafumi,
Sugeno Naoto,
Yoshida Shun,
Akiyama Tetsuya,
Fujimori Koki,
Hatakeyama Hiroyasu,
Miki Yasuo,
Tomiyama Arata,
Kawata Yasushi,
Fukuda Mitsunori,
Kawahata Ichiro,
Yamakuni Tohru,
Ezura Michinori,
Kikuchi Akio,
Baba Toru,
Takeda Atsushi,
Kanzaki Makoto,
Wakabayashi Koichi,
Okano Hideyuki,
Aoki Masashi
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.201802051r
Subject(s) - endocytic cycle , dopamine transporter , dopaminergic , extracellular , microbiology and biotechnology , endocytosis , dopamine , biology , dopamine plasma membrane transport proteins , catecholaminergic , neuroscience , chemistry , cell , biochemistry
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