Generation of new mouse model for Parkinson's disease(Fostering Joint International Research)

2017 Fiscal Year Final Research Report

• Project/Area Number: 15KK0354
• Research Category: Fund for the Promotion of Joint International Research (Fostering Joint International Research)
• Allocation Type: Multi-year Fund
• Research Field: Neurology
• Research Institution: Juntendo University
• Principal Investigator: FUNAYAMA Manabu 順天堂大学, 医学部, 准教授 (70468578)
• Research Collaborator: Sue Carolyn M シドニー大学, Kolling研究所・医学部, 教授
• Project Period (FY): 2015 – 2017
• Keywords: パーキンソン病 / ミトコンドリア / CHCHD2 / 遺伝 / 呼吸鎖複合体 / 神経分化

Outline of Final Research Achievements

We recently identified CHCHD2 mutations as a novel gene associated with autosomal dominant Parkinson’s disease (PD). CHCHD2 is localized to mitochondria and linked to mitochondrial complex IV function, however, its pathogenic mechanisms remain largely unknown. To elucidate the involvement between CHCHD2 and mitochondria, we generated CHCHD2-KO cells using CRISPR/Cas9 techniques, and performed mitochondrial phenotyping. Steady state ATP level and ATP synthesis rate were dramatically decreased in CHCHD2-KO cells. Steady state ATP level was partially rescued by overexpression of wildtype CHCHD2, but not by PD linked mutants of CHCHD2 (T61I and R145Q). Mitochondrial membrane potential, ROS, and superoxide were markedly and significantly increased in CHCHD2-KO cells. In conclusion, Loss of CHCHD2 impairs multiple mitochondrial functions and CHCHD2 KO cells may provide a useful cell model for understanding CHCHD2 function and pathophysiology of CHCHD2 mutations and PD.

Free Research Field

分子遺伝学