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Krios III-Titan Krios III at Diamond	Age-dependent formation of TMEM106B amyloid filaments in human brains Manuel Schweighauser , Diana Arseni , Mehtap Bacioglu , Melissa Huang , Sofia Lovestam , Yang Shi , Yang Yang , Wenjuan Zhang , Abhay Kotecha , Holly J. Garringer , Ruben Vidal , Grace I. Hallin , 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 Nature DOI: 10.1038/s41586-022-04650-z Diamond Proposal Number(s): [17434, 23268] Open Access Show Abstract ▼ Abstract: Many age-dependent neurodegenerative diseases, like Alzheimer’s and Parkinson’s, are characterised by abundant inclusions of amyloid filaments. Filamentous inclusions of the proteins tau, amyloid-β (Aβ), α-synuclein and TDP-43 are the most common1,2. Here, we used electron cryo-microscopy (cryo-EM) structure determination 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 cryo-EM structures of TMEM106B filaments from a number of brain regions of 22 individuals with abundant amyloid deposits, including sporadic and inherited tauopathies, Aβ-amyloidoses, synucleinopathies and TDP-43 proteinopathies, as well as from the frontal cortex of 3 neurologically normal individuals with no or only 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 for the C-terminal region of TMEM106B. The identification of TMEM106B filaments in the brains of older, but not younger, neurologically normal individuals indicates that they form in an age-dependent manner.	Mar 2022

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Krios III-Titan Krios III at Diamond

Age-dependent formation of TMEM106B amyloid filaments in human brains