常染色体显性 VCP 功能降低突变会损害 PHF-tau 的解聚。
Autosomal dominant VCP hypomorph mutation impairs disaggregation of PHF-tau.
机构信息
Translational Neuropathology Research Laboratory, Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, PA, USA.
Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, PA, USA.
出版信息
Science. 2020 Nov 20;370(6519). doi: 10.1126/science.aay8826. Epub 2020 Oct 1.
Neurodegeneration in Alzheimer's disease (AD) is closely associated with the accumulation of pathologic tau aggregates in the form of neurofibrillary tangles. We found that a p.Asp395Gly mutation in (valosin-containing protein) was associated with dementia characterized neuropathologically by neuronal vacuoles and neurofibrillary tangles. Moreover, VCP appeared to exhibit tau disaggregase activity in vitro, which was impaired by the p.Asp395Gly mutation. Additionally, intracerebral microinjection of pathologic tau led to increased tau aggregates in mice in which p.Asp395Gly mice was knocked in, as compared with injected wild-type mice. These findings suggest that p.Asp395Gly is an autosomal-dominant genetic mutation associated with neurofibrillary degeneration in part owing to reduced tau disaggregation, raising the possibility that VCP may represent a therapeutic target for the treatment of AD.
阿尔茨海默病（AD）中的神经退行性变与病理性 tau 聚集体的积累密切相关，其形式为神经纤维缠结。我们发现，载脂蛋白（valosin-containing protein）中的一个 p.Asp395Gly 突变与神经病理学特征为神经元空泡和神经纤维缠结的痴呆症有关。此外，VCP 在体外表现出 tau 解聚酶活性，而 p.Asp395Gly 突变使其受损。此外，与注射野生型小鼠相比，向 p.Asp395Gly 敲入小鼠的脑内微注射病理性 tau 导致 tau 聚集体增加。这些发现表明，p.Asp395Gly 是一种常染色体显性遗传突变，部分原因是 tau 解聚减少导致神经纤维变性，这增加了 VCP 可能成为治疗 AD 的治疗靶点的可能性。
Zotero 插件