Genetic analysis of CHCHD2 in ALS cohorts

2023 Fiscal Year Final Research Report

• Project/Area Number: 20K16504
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 51030:Pathophysiologic neuroscience-related
• Research Institution: Juntendo University
• Principal Investigator: Ikeda Aya 順天堂大学, 大学院医学研究科, 助教 (70867796)
• Project Period (FY): 2020-04-01 – 2024-03-31
• Keywords: CHCHD2

Outline of Final Research Achievements

CHCHD2 P14L was dissociated form the mitochondria to the cytoplasm, which was observed in both SH-SY5Y cells as well as Drosophila dopaminergic and motor neurons. CHCHD2 P14L showed reduced mitochondria Ca2+ uptake and elevated cytoplasmic Ca2+ flux, which was observed in both SH-SY5Y cells and Drosophila neuron terminals. Moreover, elevated cytoplasmic Ca2+ promoted TDP-43 processing and insolubilization.

Free Research Field

分子遺伝学

Academic Significance and Societal Importance of the Research Achievements

CHCHD2 T61I変異の病理学的な解 析としては、CHCHD2 T61Iがα-Synucleinの異常な凝集に関わることを患者脳、iPS由来ドパ ミン神経細胞、ショウジョウバエ、マウスのモデルで示した (申請者ら. Hum Mol Genet, 2019、 Kee et al. Hum Mol Genet, 2022)。今回、CHCHD2変異がALSで発見されたことで、PDとALS発症の分子経路を同定することが期待され、ミトコンドリアを標的とした分子標的治療の開発につながる可能性がある。