Role of Hsp70 and its related molecules in neuronal death

2014 Fiscal Year Final Research Report

• Project/Area Number: 24659540
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Psychiatric science
• Research Institution: Kanazawa University
• Principal Investigator: MINABE Yoshio 金沢大学, 医学系, 教授 (60181947)
• Co-Investigator(Kenkyū-buntansha): YAMASHIMA Tetsumori 金沢大学, 医学系, 准教授 (60135077)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Keywords: 認知症

Outline of Final Research Achievements

Using the monkey experimental paradigm, previously we reported that calpain-mediated cleavage of oxidized Hsp70.1 causes neurodegeneration in the hippocampal CA1 sector. However, the molecular mechanisms of the lysosomal destabilization/stabilization have not been elucidated. To elucidate whether regulation of lysosomal ASM could affect the neuronal fate, we analyzed Hsp70.1-BMP binding and ASM activity. We showed that Hsp70.1 being localized at the lysosomal membrane, lysosomal lipid BMP levels, and the lipid binding domain of Hsp70.1 are crucial for Hsp70.1- BMP binding. Calpain activation and a concomitant decrease in the lysosomal membrane localization of Hsp70.1 and BMP levels may diminish Hsp70.1-BMP binding, resulting in decreased ASM activity and lysosomal rupture with leakage of cathepsin B into the cytosol. Regulation of ASM activation in vivo by Hsp70.1-BMP affects lysosomal stability and neuronal survival or death after ischemia/reperfusion.

Free Research Field

神経精神医学