小柯机器人

美国加州大学洛杉矶分校David S. Eisenberg课题组近期取得重要工作进展。他们发现FTLD-TDP疾病中的淀粉样纤维由TMEM106B而不是TDP-43组成。这一研究成果2022年3月28日在线发表于《自然》杂志上。

研究人员从四名患者的大脑中提取了淀粉样蛋白原纤维，代表了五个 FTLD-TDP 亚类中的四个，并通过低温电子显微镜 (cryo-EM) 确定了它们的近原子分辨率结构。出乎意料的是，检查的所有淀粉样蛋白原纤维均由跨膜蛋白106B (TMEM106B) 的135个残基C末端片段组成，这是一种溶酶体膜蛋白，以前被认为是FTLD-TDP的遗传风险因素。正如免疫金标记所揭示的，除了TMEM106B原纤维外，还存在大量非纤维状聚集的TDP-43。他们的观察证实FTLD-TDP是一种与淀粉样蛋白相关的疾病，并表明FTLD-TDP中的淀粉样蛋白变性是由TMEM106B蛋白参与的，而不是TDP-43。

据介绍，额颞叶变性 (FTLD) 是仅次于阿尔茨海默病和帕金森病的第三大常见神经退行性疾病。FTLD通常出现在45-64岁的人群中，表现为行为改变或语言技能逐渐下降。FTLD-TDP亚型的特点是有一定的临床症状和通过TAR DNA结合蛋白（TDP-43）免疫反应性检测到的病理神经元内含物。

附：英文原文

Title: Amyloid fibrils in disease FTLD-TDP are composed of TMEM106B not TDP-43

Author: Jiang, Yi Xiao, Cao, Qin, Sawaya, Michael R., Abskharon, Romany, Ge, Peng, DeTure, Michael, Dickson, Dennis W., Fu, Janine Y., Ogorzalek Loo, Rachel R., Loo, Joseph A., Eisenberg, David S.

Issue&Volume: 2022-03-28

Abstract: Frontotemporal lobar degeneration (FTLD) is the third most common neurodegenerative condition, following only Alzheimer’s and Parkinson’s diseases1. FTLD typically presents in 45-64-year-olds with behavioral changes or progressive decline of language skills2. The subtype FTLD-TDP is characterized by certain clinical symptoms and pathological neuronal inclusions detected by TAR DNA-binding protein (TDP-43) immunoreactivity3. Here, we extracted amyloid fibrils from brains of four patients, representing four out of five FTLD-TDP subclasses and determined their near-atomic resolution structures by cryogenic electron-microscopy (cryo-EM). Unexpectedly, all amyloid fibrils examined are composed of a 135-residue C-terminal fragment of transmembrane protein 106B (TMEM106B), a lysosomal membrane protein previously implicated as a genetic risk factor for FTLD-TDP4. In addition to TMEM106B fibrils, abundant non-fibrillar aggregated TDP-43 is present, as revealed by immunogold labeling. Our observations confirm that FTLD-TDP is an amyloid-involved disease and suggest that amyloid involvement in FTLD-TDP is of protein TMEM106B, rather than of TDP-43.

DOI: 10.1038/s41586-022-04670-9

Source: https://www.nature.com/articles/s41586-022-04670-9

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
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