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Age-dependent formation of TMEM106B amyloid filaments in human brains
Manuel Schweighauser # 1, Diana Arseni # 1, Mehtap Bacioglu # 2, Melissa Huang # 1, Sofia Lövestam # 1, Yang Shi # 1, Yang Yang # 1, Wenjuan Zhang 1 3, Abhay Kotecha 4, Holly J Garringer 5, Ruben Vidal 5, Grace I Hallinan 5, Kathy L Newell 5, Airi Tarutani 6, Shigeo Murayama 7, Masayuki Miyazaki 8, Yuko Saito 9, Mari Yoshida 10, Kazuko Hasegawa 11, Tammaryn Lashley 12, Tamas Revesz 12, Gabor G Kovacs 13 14, John van Swieten 15, Masaki Takao 16 17, Masato Hasegawa 6, Bernardino Ghetti 5, Maria Grazia Spillantini 2, Benjamin Ryskeldi-Falcon 1, Alexey G Murzin 1, Michel Goedert 18, Sjors H W Scheres 19
Abstract:
...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.
