Analysis of mitochondrial respiratoty regulation mechanism and its failure in neurodegenerative disease

2018 Fiscal Year Final Research Report

• Project/Area Number: 16K19037
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: General medical chemistry
• Research Institution: Okayama University
• Principal Investigator: Murata Hitoshi 岡山大学, 医歯薬学総合研究科, 講師 (90579096)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: ミトコンドリア / SARM1 / JNK / パーキンソン病

Outline of Final Research Achievements

We analyzed regulation mechanism of SARM1 involved in mitochondrial respiratory regulation. SARM1 is phosphorylated by rotenone or praquat which induces Parkinson’s disease-like symptoms. The kinase is JNK and the phosphorylation site of SARM1 is Ser548. SARM1 has an enzymatic activity to degrade NAD, and activation of SARM1 suppressed mitochondrial ATP production through degradation of NAD. The NAD degradation activity of SARM1 was attenuated by Ala mutation of Ser548. Phosphorylation levels of SARM1 in Parkinson’s disease patient derived neurons were higher than in healthy donor derived neurons, suggesting that SARM1 activation may be involved in disease progression.

Free Research Field

分子生物学

Academic Significance and Societal Importance of the Research Achievements

我々はパーキンソン病をはじめとする神経変性疾患の病態形成メカニズムを解明し、疾患の発症や進行を抑えることができる薬剤開発を目指して研究を行っている。今回我々はミトコンドリア呼吸を阻害し、神経軸索変性に関与するSARM1の研究を行い、新規にJNKを介したリン酸化制御機構を見出した。パーキンソン病患者由来の神経細胞ではSARM1のリン酸化が上昇しており、パーキンソン病の病態形成にSARM1の活性化が関与している可能性を見出した点に学術的・社会的意義がある。