Critical role of ROCK1 in AD pathogenesis via controlling lysosomal biogenesis and acidification

作者：Chenghuan Song, Wan‐Ying Huang, Pingao Zhang, Jiyun Shi, Ting Yu, Jing Wang, Yongbo Hu, Lan‐Xue Zhao, Rui Zhang, Gang Wang, Yongfang Zhang, Hongzhuan Chen, Hao Wang · 发表于：Translational Neurodegeneration · 年份：2024 · DOI：10.1186/s40035-024-00442-9 · 被引用次数：16 · 研究领域：Alzheimer's disease research and treatments、Autophagy in Disease and Therapy、Lysosomal Storage Disorders Research

BACKGROUND: Lysosomal homeostasis and functions are essential for the survival of neural cells. Impaired lysosomal biogenesis and acidification in Alzheimer's disease (AD) pathogenesis leads to proteolytic dysfunction and neurodegeneration. However, the key regulatory factors and mechanisms of lysosomal homeostasis in AD remain poorly understood. METHODS: ROCK1 expression and its co-localization with LAMP1 and SQSTM1/p62 were detected in post-mortem brains of healthy controls and AD patients. Lysosome-related fluorescence probe staining, transmission electron microscopy and immunoblotting were performed to evaluate the role of ROCK1 in lysosomal biogenesis and acidification in various neural cell types. The interaction between ROCK1 and TFEB was confirmed by surface plasmon resonance and in situ proximity ligation assay (PLA). Moreover, we performed AAV-mediated ROCK1 downregulation followed by immunofluorescence, enzyme-linked immunosorbent assay (ELISA) and behavioral tests to unveil the effects of the ROCK1-TFEB axis on lysosomes in APP/PS1 transgenic mice. RESULTS: ROCK1 level was significantly increased in the brains of AD individuals, and was positively correlated with lysosomal markers and Aβ. Lysosomal proteolysis was largely impaired by the high abundance of ROCK1, while ROCK1 knockdown mitigated the lysosomal dysfunction in neurons and microglia. Moreover, we verified ROCK1 as a previously unknown upstream kinase of TFEB independent of m-TOR or GSK-3β. ROCK1 elevati...