A novel therapeutic target for neurological disoders by inhibition of GAPDH aggregation

2015 Fiscal Year Final Research Report

• Project/Area Number: 25450428
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Veterinary medical science
• Research Institution: Osaka Prefecture University
• Principal Investigator: Nakajima Hidemitsu 大阪府立大学, 生命環境科学研究科(系), 准教授 (30405360)
• Co-Investigator(Kenkyū-buntansha): KUWAMURA Mitsuru 大阪府立大学, 生命環境科学研究科・獣医学専攻, 准教授 (20244668)
• Co-Investigator(Renkei-kenkyūsha): YUBA Eiji 大阪府立大学, 工学研究科, 助教 (80582296)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Keywords: 脳神経疾患 / ＧＡＰＤＨ / アルツハイマー病 / 脳卒中 / 酸化ストレス / 創薬 / ペプチドミミック / 凝集阻害剤

Outline of Final Research Achievements

Glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a homotetrameric protein that also mediates cell death under oxidative stresses. We previously reported that intermolecular disulfide-bonding GAPDH aggregates through oxidation of the active site cysteine (Cys-152) participate in oxidative stress-induced cell death. We also revealed that the active site cysteine-null GAPDH (C152A-GAPDH) rescues oxidative stress-induced neuronal cell death in a dominant negative manner via the formation of these hybrid tetramer both in vitro and in vivo. Here we report that this dominant negative C152A-GAPDH mutant against endogenous GAPDH aggregation in response to oxidative stress ameliorated neuronal cell death in neurological models using a specific inhibitor of GAPDH aggregation (GAI-X) exerted decrease of neurological dysfunctions. These findings provide a therapeutic avenue of new drug target for the brain damages such as Stroke and Alzheimer disease.

Free Research Field

獣医薬理学