ジャーナル: Nature / 年: 2022 タイトル: Age-dependent formation of TMEM106B amyloid filaments in human brains. 著者: Manuel Schweighauser / Diana Arseni / Mehtap Bacioglu / Melissa Huang / Sofia Lövestam / Yang Shi / Yang Yang / Wenjuan Zhang / Abhay Kotecha / Holly J Garringer / Ruben Vidal / Grace I ...著者: Manuel Schweighauser / Diana Arseni / Mehtap Bacioglu / Melissa Huang / Sofia Lövestam / Yang Shi / Yang Yang / Wenjuan Zhang / Abhay Kotecha / Holly J Garringer / Ruben Vidal / Grace I Hallinan / Kathy L Newell / Airi Tarutani / Shigeo Murayama / Masayuki Miyazaki / Yuko Saito / Mari Yoshida / Kazuko Hasegawa / Tammaryn Lashley / Tamas Revesz / Gabor G Kovacs / John van Swieten / Masaki Takao / Masato Hasegawa / Bernardino Ghetti / Maria Grazia Spillantini / Benjamin Ryskeldi-Falcon / Alexey G Murzin / Michel Goedert / Sjors H W Scheres / 要旨: 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- ...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.