Analysis of autophagic degradation of alpha-synuclein by p62-phosphorylation

2017 Fiscal Year Final Research Report

• Project/Area Number: 15K09320
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurology
• Research Institution: Kyoto Prefectural University of Medicine
• Principal Investigator: Watanabe Yoshihisa 京都府立医科大学, 医学(系)研究科(研究院), 講師 (50363990)
• Co-Investigator(Kenkyū-buntansha): 徳田 隆彦 京都府立医科大学, 医学(系)研究科(研究院), 教授 (80242692)
• Co-Investigator(Renkei-kenkyūsha): TSUJIMURA Atsushi 京都府立医科大学, 医学研究科, 助教 (50236890)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Keywords: p62 / オートファジー / HSF1 / パーキンソン病 / α-シヌクレイン

Outline of Final Research Achievements

We studied the regulation of phosphorylation of autophagy receptor p62. Phosphorylation of p62 at Ser349 and Ser403 was suppressed by inhibition or gene knockout of heat shock factor 1 (HSF1). And then, they decreased inclusion formation of ubiquitinated proteins. Moreover, we identified that casein kinase 1 phosphorylated Ser-349 by the phosphorylation screening assay. HSP90 inhibitors also suppressed phosphorylation of p62. However, knock down of HSP90AA1 and HSP90AB1 could not reproduce this suppression, suggesting that HSP90 inhibitors suppress its phosphorylation through an indirect mechanism.
Next, we examined p62 phosphorylation in HEK293 cells or mice striatum transformed with α-synuclein fibrils. p62 colocalized to α-Synuclein inclusions was phosphorylated at Ser349 but not at Ser403.

Free Research Field

神経内科学