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阿尔茨海默病与肌萎缩侧索硬化症偶联的关键肽片段之间的催化串扰
作者:小柯机器人 发布时间:2021/2/28 19:15:56

美国加州大学圣芭芭拉分校Michael T. Bowers研究小组近日取得一项新成果。经过不懈努力,他们提出了阿尔茨海默病与肌萎缩性侧索硬化症的关键肽片段之间的催化交叉作用。 相关论文发表在2021年2月23日出版的《美国化学会杂志》上。

本文研究了TDP-43、TDP-43307-319淀粉样核与神经毒性生理观察的Aβ、Aβ25-35片段之间的相互作用。利用离子迁移质谱技术与原子力显微镜和分子动力学模拟相结合,该课题组人员研究了哪些低聚物参与了这两种不同蛋白质系统的种子聚集,并深入了解了由这些相互作用引发和产生的结构。

将Aβ25-35与有毒野生型TDP-43307-319肽和无毒合成TDP-43307-319突变体G314V混合进行研究。他们的发现证实了TDP-43307-319 WT单体在加速Aβ25-35聚集成毒性圆柱状和β桶状的强烈催化作用。这种观察的速度和特异性都是前所未有的。

有趣的是,TDP-43307-319的无毒G314V突变体和WT TDP-43307-319的二聚体或更高阶低聚物不促进Aβ25-35的聚集,而是解离了预先形成的Aβ25-35的有毒高阶低聚物。本文报告了这些不同行为的原因。

研究人员表示,蛋白质聚集是显著的神经退行性疾病的共同特征,被认为是由于单一肽或蛋白质的组装。最近的研究对这一观点提出了质疑,并提出一些蛋白质可能参与促进和放大疾病。例如,大脑中发现了与肌萎缩性侧索硬化症相关的TDP-43蛋白,以及与阿尔茨海默病相关的Aβ集合,与TDP-43阴性的阿尔茨海默病患者相比,显示TDP-43存在的患者表现出认知障碍的可能性高出10倍。

附:英文原文

Title: Catalytic Cross Talk between Key Peptide Fragments That Couple Alzheimer’s Disease with Amyotrophic Lateral Sclerosis

Author: Veronica Laos, Dezmond Bishop, Pritam Ganguly, Grace Schonfeld, Ellen Trapp, Kristi Lazar Cantrell, Steven K. Buratto, Joan-Emma Shea, Michael T. Bowers

Issue&Volume: February 23, 2021

Abstract: Protein aggregation is a common feature in prominent neurodegenerative diseases, usually thought to be due to the assembly of a single peptide or protein. Recent studies have challenged this notion and suggested several proteins may be involved in promoting and amplifying disease. For example, the TDP-43 protein associated with Amyotrophic Lateral Sclerosis has been found in the brain along with Aβ assemblies associated with Alzheimer’s disease, and those patients that show the presence of TDP-43 are 10 times more likely to demonstrate cognitive impairment compared to TDP-43-negative Alzheimer’s patients. Here we examine the interactions between the amyloidogenic core of TDP-43, TDP-43307-319, and a neurotoxic physiologically observed fragment of Aβ, Aβ25-35. Utilizing ion mobility mass spectrometry in concert with atomic force microscopy and molecular dynamics simulations, we investigate which oligomers are involved in seeding aggregation across these two different protein systems and gain insight into which structures initiate and result from these interactions. Studies were conducted by mixing Aβ25-35 with the toxic wild type TDP-43307-319 peptide and with the nontoxic synthetic TDP-43307-319 mutant, G314V. Our findings identify a strong catalytic effect of TDP-43307-319 WT monomer in the acceleration of Aβ25-35 aggregation to its toxic cylindrin and β barrel forms. This observation is unprecedented in both its speed and specificity. Interestingly, the nontoxic G314V mutant of TDP-43307-319 and dimers or higher order oligomers of WT TDP-43307-319 do not promote aggregation of Aβ25-35 but rather dissociate preformed toxic higher order oligomers of Aβ25-35. Reasons for these very different behaviors are reported.

DOI: 10.1021/jacs.0c12729

Source: https://pubs.acs.org/doi/10.1021/jacs.0c12729

 

期刊信息

JACS:《美国化学会志》,创刊于1879年。隶属于美国化学会,最新IF:14.612
官方网址:https://pubs.acs.org/journal/jacsat
投稿链接:https://acsparagonplus.acs.org/psweb/loginForm?code=1000