Inhibition of S1P receptor signal transduction by extracellular alpha-synuclein

• Project/Area Number: 15K07930
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Biological pharmacy
• Research Institution: Kobe University
• Principal Investigator: OKADA TARO 神戸大学, 医学研究科, 准教授 (80304088)
• Project Period (FY): 2015-10-21 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2015: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: α－シヌクレイン / S1P受容体 / パーキンソン病 / S1P / スフィンゴシン１－リン酸 / スフィンゴ脂質

Outline of Final Research Achievements

Alpha-synuclein (ASN) is considered to be involved in the pathogenesis of Parkinson's disease. ASN is know to be localized outside of neurons but its physiological and/or pathological relevance has not known. In this study I showed extracellular ASN inhibits S1P1 receptor-G protein coupling for the first time. Interestingly the effect of ASN was specific to S1P1 receptor and S1P2 receptor-G protein coupling was not inhibited by extracellular ASN at all. Majority of S1P1 receptor is localized in raft fraction in the cells and extracellular ASN treatment cause "exit" of S1P1 receptor from the raft fraction. These results are important because specific action of extracellular ASN has not been known and we already reported that S1P1 receptor plays important role in hippocampal neurons.

Research Products

• [Journal Article] Extracellular α-synuclein drives sphingosine 1-phosphate receptor subtype 1 out of lipid rafts, leading to impaired inhibitory G protein signaling. (2018)
  • Author(s): Badawy SMM, Okada T, Kajimoto T, Hirase M, Matovelo SA, Nakamura S, Yoshida D, Ijuin T, Nakamura SI.
  • Journal Title: Journal of Biological Chemistry Volume: in press Issue: 21 Pages: 8208-8216
  • DOI: 10.1074/jbc.ra118.001986
  • NAID: 120006554634
  • Peer Reviewed / Open Access
• [Journal Article] Involvement of Gβγ subunits of Gi protein coupled with S1P receptor on multivesicular endosomes in F-actin formation and cargo sorting into exosomes (2018)
  • Author(s): Kajimoto, T., Mohamed, N.N.I., Badawy, S.M.M., Matovelo, S.A., Hirase, M., Nakamura, S., Yoshida, D., Okada, T., Ijuin, T., Nakamura, S.
  • Journal Title: Journal of Biological Chemistry Volume: 293 Issue: 1 Pages: 245-253
  • DOI: 10.1074/jbc.m117.808733
  • NAID: 120006554633
  • Peer Reviewed
• [Journal Article] DHHC5-mediated palmitoylation of S1P receptor subtype 1 determines G-protein coupling (2017)
  • Author(s): Badawy SMM, Okada T, Kajimoto T, Ijuin T, Nakamura SI.
  • Journal Title: Scientific Reports Volume: 7 Issue: 1 Pages: 16552-16552
  • DOI: 10.1038/s41598-017-16457-4
  • NAID: 120006380402
  • Peer Reviewed / Open Access
• [Journal Article] Extracellular α-synuclein induces sphingosine 1-phosphate receptor subtype 1 uncoupled from inhibitory G-protein leaving β-arrestin signal intact. (2017)
  • Author(s): Zhang L, Okada T, Badawy SM, Hirai C, Kajimoto T, Nakamura SI.
  • Journal Title: Scientific Reports Volume: 7 Issue: 1 Pages: 44248-44248
  • DOI: 10.1038/srep44248
  • NAID: 120006380401
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Impairment of PDGF-induced chemotaxis by extracellular α-synuclein through selective inhibition of Rac1 activation (2016)
  • Author(s): Okada, T., Hirai, C., Badawy, S., Zhang, L., Kajimoto, T., Nakamura, SI.
  • Journal Title: Scientific Reports Volume: 6 Issue: 1 Pages: 37810-37810
  • DOI: 10.1038/srep37810
  • NAID: 120005898707
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] High expression of Mcl-1L via the MEK-ERK-phospho-STAT3 (Ser727) pathway protects melanocytes and melanoma from UVB-induced apoptosis. (2016)
  • Author(s): Fukumoto-T, Iwasaki-T, Okada-T, Hashimoto-T, Moon-Y, Sakaguchi-M, Fukami-Y, Nishigori-C, Oka-M.
  • Journal Title: Genes Cells. Volume: 21 Issue: 2 Pages: 185-199
  • DOI: 10.1111/gtc.12330
  • Peer Reviewed / Open Access
• [Remarks] 神戸大学医学部生化学分野（中村研）ホームページ
  • URL: http://www.med.kobe-u.ac.jp/biochemistry/Home.html
• [Remarks] 神戸大学医学研究生化学分野
  • URL: http://www.med.kobe-u.ac.jp/biochemistry/Home.html
• [Remarks] 神戸大学医学部生化学分野
  • URL: http://www.med.kobe-u.ac.jp/biochemistry/Home.html