Homotypic fibrillization of TMEM106B across diverse neurodegenerative diseases.
Homotypic fibrillization of TMEM106B across diverse neurodegenerative diseases.
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DOI：
10.1016/j.cell.2022.02.026
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发表时间：
2022-04-14
期刊：
影响因子：
64.5
通讯作者：
Fitzpatrick, Anthony W. P.
中科院分区：
文献类型：
--
作者：
Chang, Andrew;Xiang, Xinyu;Wang, Jing;Lee, Carolyn;Arakhamia, Tamta;Simjanoska, Marija;Wang, Chi;Carlomagno, Yari;Zhang, Guoan;Dhingra, Shikhar;Thierry, Manon;Perneel, Jolien;Heeman, Bavo;Forgrave, Lauren M.;DeTure, Michael;DeMarco, Mari L.;Cook, Casey N.;Rademakers, Rosa;Dickson, Dennis W.;Petrucelli, Leonard;Stowell, Michael H. B.;Mackenzie, Ian R. A.;Fitzpatrick, Anthony W. P.
疾病特异性蛋白质的错误折叠和聚集，导致丝状细胞内含物的形成，是神经退行性疾病的标志，具有特征性细丝结构或构象异构体，定义了每种蛋白质病。在这里，我们表明，以前未解决的淀粉样蛋白纤维组成的135个氨基酸的TMEM 106 B的C-末端片段是一个常见的发现，在不同的人类神经退行性疾病，包括案件的特征是异常聚集的TDP-43，tau，或α-突触核蛋白蛋白。冷冻电子显微镜和质谱的组合用于以2.7 μ m的分辨率解析来自患有具有TDP-43病理学的额颞叶变性（FTLD-TDP，N=8）、进行性核上性麻痹（PSP，N=2）或路易体痴呆（DLB，N=1）的死后人脑组织的TMEM 106 B原纤维的结构。由TMEM 106 B（一种溶酶体/内体蛋白）组成的丰富淀粉样蛋白原纤维与广泛的衰弱性人类疾病的共性表明可能引发或加速神经变性的共享纤维化途径。来自患有多种神经退行性疾病的死后人脑的不溶性淀粉样蛋白原纤维的基于Cryo-EM和质谱的蛋白质组学揭示了内溶酶体膜蛋白TMEM 106 B的广泛的纤维化，指向不同蛋白质病之间的潜在致病性共性。
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 comprised 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 cryo-electron microscopy and mass spectrometry was used to solve the structures of TMEM106B fibrils at a resolution of 2.7 Å 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. Cryo-EM and mass spectrometry-based proteomics of insoluble amyloid fibrils derived from postmortem human brains afflicted with diverse neurodegenerative diseases reveals widespread fibrillization of an endolysosomal membrane protein, TMEM106B, pointing towards a potentially pathogenic commonality between distinct proteinopathies.
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影响因子：
6.8
作者：
Chatterjee P;Pedrini S;Stoops E;Goozee K;Villemagne VL;Asih PR;Verberk IMW;Dave P;Taddei K;Sohrabi HR;Zetterberg H;Blennow K;Teunissen CE;Vanderstichele HM;Martins RN
通讯作者：
Martins RN
影响因子：
12.7
作者：
Feng T;Lacrampe A;Hu F
通讯作者：
Hu F
影响因子：
64.8
作者：
Arseni D;Hasegawa M;Murzin AG;Kametani F;Arai M;Yoshida M;Ryskeldi-Falcon B
通讯作者：
Ryskeldi-Falcon B
DOI：
10.1107/s2059798318006551
发表时间：
2018-06-01
期刊：
Acta crystallographica. Section D, Structural biology
影响因子：
--
作者：
Afonine PV;Poon BK;Read RJ;Sobolev OV;Terwilliger TC;Urzhumtsev A;Adams PD
通讯作者：
Adams PD
影响因子：
64.8
作者：
Baker, Matt;Mackenzie, Ian R.;Hutton, Mike
通讯作者：
Hutton, Mike