Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, 430060, China.
Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, 430060, China; Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, 30322, USA.
Prog Neurobiol. 2021 Aug;203:102074. doi: 10.1016/j.pneurobio.2021.102074. Epub 2021 May 13.
Neurite deficits and synaptic dysfunction contribute to cognitive impairments in Alzheimer's disease (AD). However, the underlying molecular mechanisms remain unclear. Here, we show that γ-adducin, a cytoskeleton-associated protein that assembles the spectrin-actin framework, is cleaved by a lysosomal cysteine proteinase named asparagine endopeptidase (AEP). AEP is upregulated and activated during aging and cleaves γ-adducin at N357, disrupting spectrin-actin assembly. Moreover, γ-adducin (1-357) fragment downregulates the expression of Rac2, leading to defects in neurite outgrowth. Expression of the γ-adducin (1-357) fragment in the hippocampus of tau P301S transgenic mice resulted in significant AD-like pathology and cognitive deficits. In summary, AEP-mediated fragmentation of γ-adducin plays a vital role in AD. Blocking the activity of AEP might be a novel therapeutic target for AD.
神经突缺失和突触功能障碍导致阿尔茨海默病（AD）的认知障碍。然而，其潜在的分子机制尚不清楚。在这里，我们表明，γ-辅肌动蛋白是一种细胞骨架相关蛋白，可组装血影蛋白-肌动蛋白框架，被一种溶酶体半胱氨酸蛋白酶即天冬酰胺内肽酶（AEP）切割。AEP 在衰老过程中上调和激活，并在 N357 处切割 γ-辅肌动蛋白，破坏血影蛋白-肌动蛋白的组装。此外，γ-辅肌动蛋白（1-357）片段下调 Rac2 的表达，导致神经突生长缺陷。γ-辅肌动蛋白（1-357）片段在 tau P301S 转基因小鼠海马中的表达导致明显的 AD 样病理学和认知障碍。总之，AEP 介导的 γ-辅肌动蛋白的片段化在 AD 中起着至关重要的作用。阻断 AEP 的活性可能是 AD 的一种新的治疗靶点。
