TY - JOUR
T1 - Extracellular α-synuclein enters dopaminergic cells by modulating flotillin-1–assisted dopamine transporter endocytosis
AU - Kobayashi, Junpei
AU - Hasegawa, Takafumi
AU - Sugeno, Naoto
AU - Yoshida, Shun
AU - Akiyama, Tetsuya
AU - Fujimori, Koki
AU - Hatakeyama, Hiroyasu
AU - Miki, Yasuo
AU - Tomiyama, Arata
AU - Kawata, Yasushi
AU - Fukuda, Mitsunori
AU - Kawahata, Ichiro
AU - Yamakuni, Tohru
AU - Ezura, Michinori
AU - Kikuchi, Akio
AU - Baba, Toru
AU - Takeda, Atsushi
AU - Kanzaki, Makoto
AU - Wakabayashi, Koichi
AU - Okano, Hideyuki
AU - Aoki, Masashi
N1 - Funding Information:
The authors thank Tomoe Ito and Shun Ishiyama (Division of Neurology, Department of Neuroscience and Sensory Organs, Tohoku University Graduate School of Medicine) for excellent technical assistance. This work was supported in part by a Grant-in-Aid for Scientific Research (C) (Grant 17K09744 to T.H.), a Grant-in-Aid for Scientific Research on Innovative Areas (Brain Protein Aging and Dementia Control) (Grant 15H01550 to T.H.), and a Grant-in-Aid for Research Activity Start-Up (Grant 18H062060 to J.K.) from the Ministry of Education, Culture, Sports, Science, and Technology (MEXT). This work was also supported by a Grant-in-Aid for the Research Committee for Ataxic Diseases (to A.T.), a Grant-in-Aid for Practical Research Projects for Rare/Intractable Diseases (Grants 17ek0109222h0001 and 18ek0109222h0002 to T.H.), a Grant-in-Aid for Translational Research Network Program (Tohoku University) (Grant 161m0103007j0005 to T.H.), a Grant-in-Aid for the Strategic Research Program for Brain Sciences (Grants 17dm0107071 and 18dm0107071 to T.H.; 17dm0107072 and 18dm0107072 to A.T.; and 18dm0107073 to Y.K), the Acceleration Program for Intractable Diseases Research utilizing Disease-specific iPSCs (Grant 19bm0804003h0003 to H.O.) from the Japan Agency for Medical Research and Development (AMED), and Novartis Pharma Research grants (to T.H.). The authors declare no conflicts of interest.
Publisher Copyright:
© FASEB
PY - 2019/9/1
Y1 - 2019/9/1
N2 - 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.
AB - 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.
KW - DAT
KW - Lewy body
KW - Parkinson's disease
KW - endocytosis
KW - endosome
UR - http://www.scopus.com/inward/record.url?scp=85071788368&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85071788368&partnerID=8YFLogxK
U2 - 10.1096/fj.201802051R
DO - 10.1096/fj.201802051R
M3 - Article
C2 - 31211923
AN - SCOPUS:85071788368
SN - 0892-6638
VL - 33
SP - 10240
EP - 10256
JO - FASEB Journal
JF - FASEB Journal
IS - 9
ER -