小柯机器人

美国哥伦比亚大学Anthony W.P. Fitzpatrick等研究人员合作发现TMEM106B在多种神经退行性疾病中的同型纤维形成。相关论文于2022年3月4日在线发表于国际学术期刊《细胞》。

研究人员发现，由TMEM106B的135个氨基酸的C端片段组成的淀粉样纤维是不同人类神经退行性疾病的共同发现，包括以TDP-43、tau或α-synuclein蛋白的异常聚集为特征的病例。冷冻电子显微镜和质谱分析相结合，解析了TMEM106B纤维的结构问题，其分辨率为2.7埃，这些样品来自患有TDP-43病理的额颞叶变性（FTLD-TDP，n=8）、进行性核上麻痹（PSP，n=2）或路易体痴呆（DLB，n=1）的死后人类大脑组织。由TMEM106B（一种溶酶体/内体蛋白）组成的丰富淀粉样纤维与广泛使人衰弱的疾病的共性提示了一个共同的纤维形成途径，可能会启动或加速神经退化。

据了解，疾病特定蛋白的错误折叠和聚集，导致丝状细胞内含物的形成，是神经退行性疾病的一个标志，其特征性的丝状结构或构象体定义了每个蛋白病。

附：英文原文

Title: Homotypic fibrillization of TMEM106B across diverse neurodegenerative diseases

Author: Andrew Chang, Xinyu Xiang, Jing Wang, Carolyn Lee, Tamta Arakhamia, Marija Simjanoska, Chi Wang, Yari Carlomagno, Guoan Zhang, Shikhar Dhingra, Manon Thierry, Jolien Perneel, Bavo Heeman, Lauren M. Forgrave, Michael DeTure, Mari L. DeMarco, Casey N. Cook, Rosa Rademakers, Dennis W. Dickson, Leonard Petrucelli, Michael H.B. Stowell, Ian R.A. Mackenzie, Anthony W.P. Fitzpatrick

Issue&Volume: 2022-03-04

Abstract: Misfolding and aggregation of disease-specific proteins, resulting in the formation of filamentous cellular inclusions, is a hallmark of neurodegenerative disease with characteristic filament structures, or conformers, defining each proteinopathy. Here we show that a previously unsolved amyloid fibril composed of a 135 amino acid C-terminal fragment of TMEM106B is a common finding in distinct human neurodegenerative diseases, including cases characterized by abnormal aggregation of TDP-43, tau, or α-synuclein protein. A combination of cryoelectron microscopy and mass spectrometry was used to solve the structures of TMEM106B fibrils at a resolution of 2.7 from postmortem human brain tissue afflicted with frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP, n = 8), progressive supranuclear palsy (PSP, n = 2), or dementia with Lewy bodies (DLB, n = 1). The commonality of abundant amyloid fibrils composed of TMEM106B, a lysosomal/endosomal protein, to a broad range of debilitating human disorders indicates a shared fibrillization pathway that may initiate or accelerate neurodegeneration.

DOI: 10.1016/j.cell.2022.02.026

Source: https://www.cell.com/cell/fulltext/S0092-8674(22)00259-8