Age-dependent formation of TMEM106B amyloid filaments in human brains

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 LashleyTamas 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*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

18 Citations (Scopus)
6 Downloads (Pure)

Abstract

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 common1,2. 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.

Original languageEnglish
Pages (from-to)310-314
Number of pages5
JournalNature
Volume605
Issue number7909
Early online date28 Mar 2022
DOIs
Publication statusPublished - 12 May 2022

Bibliographical note

© 2022. The Author(s).

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