Age-dependent formation of TMEM106B amyloid filaments in human brain

Manuel Schweighauser; Diana Arseni; Mehtap Bacioglu; Melissa Huang; Sofia Lövestam; Yang Shi; Yang Yang; Wenjuan Zhang; Abhay Kotecha; Holly J. Garringer; Rubén Vidal; Grace I. Hallinan; Kathy L. Newell; Airi Tarutani; Shigeo Murayama; Masayuki Miyazaki; Yuko Saito; Mari Yoshida; Kazuko Hasegawa; Tammaryn Lashley; Tamás Révész; Gábor Géza Kovács; John Cornelis Van Swieten; Masaki Takao; Masato Hasegawa; Bernardino Francesco Ghetti; Maria Grazia Spillantini; Benjamin Falcon; Alexey G. Murzin; Michel Goedert

doi:10.1038/s41586-022-04650-z

NeuroscienceNatureMar 28, 2022

Peer-reviewed journal article

Age-dependent formation of TMEM106B amyloid filaments in human brain

Manuel Schweighauser iD, Diana Arseni iD, Mehtap Bacioglu iD, Melissa Huang iD, Sofia Lövestam iD, Yang Shi iD, Yang Yang iD, Wenjuan Zhang iD, Abhay Kotecha iD, Holly J. Garringer iD, Rubén Vidal iD, Grace I. Hallinan iD, Kathy L. Newell iD, Airi Tarutani iD, Shigeo Murayama iD, Masayuki Miyazaki, Yuko Saito iD, Mari Yoshida iD, Kazuko Hasegawa, Tammaryn Lashley iD, Tamás Révész iD, Gábor Géza Kovács iD, John Cornelis Van Swieten iD, Masaki Takao iD, Masato Hasegawa iD, , Sjors H. W. Scheres iD

Abstract

Many age-dependent neurodegenerative diseases, like Alzheimers and Parkinsons, are characterised by abundant inclusions of amyloid filaments. Filamentous inclusions of the proteins tau, amyloid-{beta} (A{beta}), -synuclein and TDP-43 are the most common. 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 the human brain. We solved cryo-EM structures of TMEM106B filaments from the brains of 22 individuals with neurodegenerative conditions, including sporadic and inherited tauopathies, A{beta}-amyloidoses, synucleinopathies and TDP-43opathies, as well as from the brains of two neurologically normal individuals. We observed three different TMEM106B folds, with no clear relationship between folds and diseases. The presence of TMEM106B filaments correlated with that of a 29 kDa sarkosyl-insoluble fragment of the protein on Western blots. The presence of TMEM106B filaments in the brains of older, but not younger, neurologically normal individuals indicates that they form in an age-dependent manner.

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