Neuronal HAP1 functions as a key molecule of intrinsic neuroprotectants in aging and neuropathological conditions

Research Project

Project/Area Number	15K08154
Research Category	Grant-in-Aid for Scientific Research (C)
Allocation Type	Multi-year Fund
Section	一般
Research Field	General anatomy (including histology/embryology)
Research Institution	Yamaguchi University
Principal Investigator	FUJINAGA Ryutaro 山口大学, 大学院医学系研究科, 講師 (30335723)
Co-Investigator(Kenkyū-buntansha)	篠田晃山口大学, 大学院医学系研究科, 教授 (40192108)
Project Period (FY)	2015-04-01 – 2018-03-31
Project Status	Completed (Fiscal Year 2017)
Budget Amount *help	¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000) Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000) Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000) Fiscal Year 2015: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Keywords	アポトーシス / 老化 / ミトコンドリア / ハンチントン病 / ノックアウトマウス / プロテアソーム / ゲノム編集 / タイムラプス
Outline of Final Research Achievements	Huntingtin-associated protein 1 (HAP1) is a core component of the stigmoid body (STB). In this study, we found that subcellular HAP1 morphology was changed from STB formation into cytoplasmic reticulo-granular structure surrounding mitochondria after treatment of proteasome inhibitor (PI) in HAP1-transfected cells. The drug also induced interaction of HAP1 and mitochondrial porin protein VDAC1 on mitochondria. PI-induced apoptosis was shown to be clearly suppressed by over-expression of HAP1 with cytoplasmic reticulo-granular structure in terms of reduction of cytoplasmic cytochrome C release and caspase-3 activation. Rather, PI-induced apoptosis was enhanced in CRISPR-Cas9-mediated Hap1-knock out mice established here. These results indicated that HAP1 is a intrinsic neuroprotectant particularly in proteasome-activity-reduced condition, which is closely related to aged conditions in the brain.