自噬
生物
细胞生物学
HDAC6型
死孢子体1
下调和上调
组蛋白脱乙酰基酶
组蛋白
生物化学
细胞凋亡
基因
作者
Qian Liu,Xin Wang,Zhi‐Ting Fang,Junning Zhao,X RUI,Bing-Ge Zhang,Ye He,Ruijuan Liu,Jian Chen,Gaoshang Chai,Gong‐Ping Liu
标识
DOI:10.1080/15548627.2024.2431472
摘要
Alzheimer disease (AD), a prevalent neurodegenerative condition in the elderly, is marked by a deficit in macroautophagy/autophagy, leading to intracellular MAPT/tau accumulation. While ISG15 (ISG15 ubiquitin like modifier) has been identified as a regulator of selective autophagy in ataxia telangiectasia (A-T), its role in AD remains unexplored. Our study reveals elevated ISG15 levels in the brains of patients with sporadic AD and AD models in vivo and in vitro. ISG15 overexpression in cells and the hippocampus inhibited HDAC6 (histone deacetylase 6) activity through C-terminal LRLRGG binding to HDAC6. Consequently, this increased CTTN (cortactin) acetylation, disrupted CTTN and F-actin recruitment to lysosomes, and impaired autophagosome (AP)-lysosome (LY) fusion. These disruptions led to MAPT/tau accumulation, synaptic damage, neuronal loss, and cognitive deficits. Conversely, ISG15 knockdown in our HsMAPT (human MAPT) pathology model restored HDAC6 activity, promoted AP-LY fusion, and improved cognitive function. This study identifies ISG15 as a key regulator of autophagic flux in AD, suggesting that targeting ISG15-mediated autophagy could offer therapeutic potential for AD.
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