Analysis of axonal degeneration mechanism by mitochondrial respiratory suppression in Parkinson's disease

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K07369
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 48040:Medical biochemistry-related
• Research Institution: Okayama University
• Principal Investigator: Murata Hitoshi 岡山大学, 医歯薬学域, 講師 (90579096)
• Co-Investigator(Kenkyū-buntansha): 阪口 政清 岡山大学, 医歯薬学域, 教授 (70379840) ; 浅沼 幹人 岡山大学, 医歯薬学域, 教授 (00273970)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: SARM1 / ミトコンドリア / 軸索変性 / パーキンソン病

Outline of Final Research Achievements

We analyzed the mechanism of axonal degeneration induction by mitochondrial respiratory inhibition mediated by abnormal activation of SARM1. SARM1 was activated by JNK-mediated phosphorylation and inhibited mitochondrial respiration by hydrolyzing NAD+. In order to see the effect of this pathway on the pathogenesis of Parkinson's disease (PD), we performed analysis using neurons derived from PD patients lacking the Parkin gene and rotenone that induces PD-like symptoms. Parkin deletion and exposure to rotenone increased SARM1 phosphorylation levels and increased the rate of axonal degeneration and cell death. Similar phenomena were observed in vivo, suggesting that abnormal activation of SARM1 is involved in the pathogenesis of PD.

Free Research Field

分子生物学

Academic Significance and Societal Importance of the Research Achievements

パーキンソン病は中脳黒質から線条体に軸索を投射するドーパミン作動性神経の脱落を主な原因とする神経変性疾患である。我々はミトコンドリア呼吸を阻害し、軸索変性を誘導する分子であるSARM1の解析を行い、リン酸化によるSARM1の異常活性化がパーキンソン病の病態進行に関与する可能性を示す解析結果を得た。リン酸化SARM1の機能を阻害する低分子化合物を見出したので、今後パーキンソン病の治療薬開発に繋がるように研究を更に進めていく。