In vivo involvement of chorein and autopagy

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K15746
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 52030:Psychiatry-related
• Research Institution: Kagoshima University
• Principal Investigator: Sasaki Natsuki 鹿児島大学, 医歯学域医学系, 助教 (30755252)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: 有棘赤血球舞踏病 / VPS13A / chorein / 脂肪輸送 / リポファジー

Outline of Final Research Achievements

An interaction between chorein and a protein involved in intracellular calcium ion regulation, which interacts with myosin VI, was confirmed. In HEK293 cells with VPS13A gene knockdown (VPS13A-KD) by RNAi, calcium concentration increased upon ML-SA1 stimulation. This interacting protein has been reported to be associated with autophagy, suggesting that increased calcium concentration due to autophagy impairment could be one of the molecular pathologies of chorea-acanthocytosis (ChAc). Additionally, in VPS13A-KD cells under starvation conditions, impaired fat transport and β-oxidation were observed. This suggests that the molecular pathology of ChAc includes a defect in lipophagy, a process where lipid droplets are degraded by autophagy and fatty acids are mobilized.

Free Research Field

精神神経医学

Academic Significance and Societal Importance of the Research Achievements

今回の研究では、オートファジー関連タンパク質とchoreinが相互作用し、そのchoreinの障害によって細胞内カルシウム濃度上昇しており、ChAcの神経細胞死の分子病態の一つである可能性が示唆された。また、ChAcの病態にオートファジーの中でも脂肪滴動員に関与するリポファジー障害が関与している可能性が示唆された。ChAcは精神症状を高率に呈する神経変性疾患であり、これらの新規細胞障害機構が精神疾患の病因にもなっていることが示唆された。ChAcの病態は精神疾患の病態に関わる可能性が高く、さらなる研究が望まれる。