当前位置:科学网首页 > 小柯机器人 >详情
常染色体显性VCP突变减弱了PHF-tau的错误聚集
作者:小柯机器人 发布时间:2020/10/3 22:53:11

常染色体显性VCP亚型突变减弱了PHF-tau的错误聚集,这一成果由美国宾夕法尼亚大学Edward B. Lee团队经过不懈努力而取得。该研究成果于2020年10月1日发表在《科学》上。

研究人员发现VCP中p.Asp395Gly突变与痴呆症相关,其特征在于神经元液泡和神经原纤维缠绕的神经病理学特征。

此外,VCP似乎在体外表现出tau错误聚集活性,这被p.Asp395Gly突变所削弱。另外,与注射野生型tau的小鼠相比,病理tau的脑内显微注射导致p.Asp395Gly VCP敲入小鼠tau聚集体增加。

这些发现表明,p.Asp395Gly VCP是与神经原纤维变性相关的常染色体显性遗传突变,这部分是由于tau分解减少造成的;这表明VCP可作为阿尔茨海默氏病(AD)治疗的潜在靶点。

据悉,AD的神经变性与病理性tau聚集体以神经原纤维缠绕形式的聚集密切相关。

附:英文原文

Title: Autosomal dominant VCP hypomorph mutation impairs disaggregation of PHF-tau

Author: Nabil F. Darwich, Jessica M. Phan, Boram Kim, EunRan Suh, John D. Papatriantafyllou, Lakshmi Changolkar, Aivi T. Nguyen, Caroline M. O’Rourke, Zhuohao He, Sílvia Porta, Garrett S. Gibbons, Kelvin C. Luk, Sokratis G. Papageorgiou, Murray Grossman, Lauren Massimo, David J. Irwin, Corey T. McMillan, Ilya M. Nasrallah, Camilo Toro, Geoffrey K. Aguirre, Vivianna M. Van Deerlin, Edward B. Lee

Issue&Volume: 2020/10/01

Abstract: Neurodegeneration in Alzheimer’s disease (AD) is closely associated with accumulation of pathologic tau aggregates in the form of neurofibrillary tangles. We found that a p.Asp395Gly mutation in VCP 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. Additionafsupplly, intracerebral microinjection of pathologic tau led to increased tau aggregates in p.Asp395Gly VCP knock-in mice compared to injected wild-type mice. These findings suggest that p.Asp395Gly VCP is an autosomal dominant genetic mutation associated with neurofibrillary degeneration in part due to reduced tau disaggregation, raising the possibility that VCP may represent a therapeutic target for the treatment of AD.

DOI: 10.1126/science.aay8826

Source: https://science.sciencemag.org/content/early/2020/09/30/science.aay8826

期刊信息
Science:《科学》,创刊于1880年。隶属于美国科学促进会,最新IF:41.037