The role of LRRK on autophagy and its therapeutic aplication to Parkinsonism

2017 Fiscal Year Final Research Report

• Project/Area Number: 15H04705
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Pathological medical chemistry
• Research Institution: Osaka University
• Principal Investigator: Toyofuku Toshihiko 大阪大学, 医学系研究科, 特任教授(常勤) (60322179)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Keywords: パーキンソン病 / ミトコンドリア / LRRK2

Outline of Final Research Achievements

Parkinson disease is genetically caused by mutations in LRRK2. We found that neurons expressing mutant LRRK2 decreased the mitochondrial energetics and mitochondrial calcium signaling. Mitochondrial calcium is introduced through the contact site between endoplasm (ER) and mitochondria and regulates mitochondrial energetics. LRRK2 interacted with mitochondrial ubiquitin ligases, which regulated components in the ER-mitochondrial interaction Neuron expressing mutant LRRK2 inhibited the activities of these ligases, and then accumulated components disturbed the ER-mitochondrial interaction and ER stress response, resulting in the increased ER stress and apoptotic death of neurons. The treatment with activators for PERK, one of the ER stress inducers, rescued these defects in neuron expressing mutant LRRK2. Thus, our result provides new insight for the treatment for Parkinson disease.

Free Research Field

細胞生物学