Age-dependent formation of TMEM106B amyloid filaments in human brains.
Age-dependent formation of TMEM106B amyloid filaments in human brains.
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DOI：
10.1038/s41586-022-04650-z
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发表时间：
2022-05
期刊：
影响因子：
64.8
通讯作者：
中科院分区：
文献类型：
--
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许多年龄依赖性神经退行性疾病，例如阿尔茨海默氏症和帕金森氏症，其特征是含有丰富的淀粉样蛋白丝。 tau 蛋白、β 淀粉样蛋白、α-突触核蛋白和反式反应 DNA 结合蛋白（TARDBP；也称为 TDP-43）的丝状内含物是最常见的。在这里，我们通过低温电子显微镜进行结构测定，结果表明溶酶体 II 型跨膜蛋白 106B (TMEM106B) 的残基 120-254 也在人脑中形成淀粉样蛋白丝。我们确定了 22 名具有丰富淀粉样蛋白沉积物的个体的多个大脑区域的 TMEM106B 丝结构，包括散发性和遗传性 tau 蛋白病、淀粉样蛋白-β 淀粉样变性、突触核蛋白病和 TDP-43 蛋白病引起的脑区域，以及 3 名神经功能正常但没有或仅有少量淀粉样蛋白沉积物的个体的额叶皮层的 TMEM106B 丝结构。我们观察到三个 TMEM106B 褶皱，褶皱与疾病之间没有明确的关系。 TMEM106B 丝与 29-kDa 肌糖基不溶性片段和球状细胞质内含物的存在相关，如通过对 TMEM106B 羧基末端区域特异的抗体检测到的。在神经系统正常的老年人而非年轻人的大脑中鉴定出 TMEM106B 细丝，表明它们以年龄依赖性方式形成。一项利用低温电子显微镜进行结构测定的研究鉴定并表征了人脑中的 TMEM106B 淀粉样蛋白丝，并表明它们的形成具有年龄依赖性，与疾病没有明显关联。
Many age-dependent neurodegenerative diseases, such as Alzheimer’s and Parkinson’s, are characterized by abundant inclusions of amyloid filaments. Filamentous inclusions of the proteins tau, amyloid-β, α-synuclein and transactive response DNA-binding protein (TARDBP; also known as TDP-43) are the most common. Here we used structure determination by cryogenic electron microscopy to show that residues 120–254 of the lysosomal type II transmembrane protein 106B (TMEM106B) also form amyloid filaments in human brains. We determined the structures of TMEM106B filaments from a number of brain regions of 22 individuals with abundant amyloid deposits, including those resulting from sporadic and inherited tauopathies, amyloid-β amyloidoses, synucleinopathies and TDP-43 proteinopathies, as well as from the frontal cortex of 3 individuals with normal neurology and no or only a few amyloid deposits. We observed three TMEM106B folds, with no clear relationships between folds and diseases. TMEM106B filaments correlated with the presence of a 29-kDa sarkosyl-insoluble fragment and globular cytoplasmic inclusions, as detected by an antibody specific to the carboxy-terminal region of TMEM106B. The identification of TMEM106B filaments in the brains of older, but not younger, individuals with normal neurology indicates that they form in an age-dependent manner. A study using structure determination by cryogenic electron microscopy identifies and characterizes TMEM106B amyloid filaments in human brain, and suggests that their formation is age dependent, with no obvious association with disease.
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DOI：
10.1107/s2059798319016577
发表时间：
2020-02-01
影响因子：
2.2
作者：
Scheres, Sjors H. W.
通讯作者：
Scheres, Sjors H. W.
影响因子：
3.5
作者：
Brady, Owen A.;Zheng, Yanqiu;Hu, Fenghua
通讯作者：
Hu, Fenghua
影响因子：
12.7
作者：
Feng T;Lacrampe A;Hu F
通讯作者：
Hu F
影响因子：
9.3
作者：
Rhinn, Herve;Abeliovich, Asa
通讯作者：
Abeliovich, Asa
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