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Age-dependent formation of TMEM106B amyloid filaments in human brains
DOI:
10.1038/s41586-022-04650-z
Authors:
Manuel
Schweighauser
(Medical Research Council Laboratory of Molecular Biology)
,
Diana
Arseni
(Medical Research Council Laboratory of Molecular Biology)
,
Mehtap
Bacioglu
(University of Cambridge)
,
Melissa
Huang
(Medical Research Council Laboratory of Molecular Biology)
,
Sofia
Lovestam
(Medical Research Council Laboratory of Molecular Biology)
,
Yang
Shi
(Medical Research Council Laboratory of Molecular Biology)
,
Yang
Yang
(Medical Research Council Laboratory of Molecular Biology)
,
Wenjuan
Zhang
(Medical Research Council Laboratory of Molecular Biology)
,
Abhay
Kotecha
(Thermo Fisher Scientific)
,
Holly J.
Garringer
(Indiana University School of Medicine)
,
Ruben
Vidal
(Indiana University School of Medicine)
,
Grace I.
Hallin
(Indiana University School of Medicine)
,
Kathy L.
Newell
(Indiana University School of Medicine)
,
Airi
Tarutani
(Tokyo Metropolitan Institute of Medical Science)
,
Shigeo
Murayama
(University of Osaka)
,
Masayuki
Miyazaki
(National Center Hospital (Tokyo))
,
Yuko
Saito
(Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology)
,
Mari
Yoshida
(Aichi Medical University)
,
Kazuko
Hasegawa
(Sagamihara National Hospital)
,
Tammaryn
Lashley
(UCL Queen Square Institute of Neurology)
,
Tamas
Revesz
(UCL Queen Square Institute of Neurology)
,
Gabor G.
Kovacs
(University of Toronto; Medical University of Vienna)
,
John
Van Swieten
(Erasmus Medical Centre)
,
Masaki
Takao
(National Center Hospital (Tokyo); Mihara Memorial Hospital)
,
Masato
Hasegawa
(Tokyo Metropolitan Institute of Medical Science)
,
Bernardino
Ghetti
(Indiana University School of Medicine)
,
Maria Grazia
Spillantini
(University of Cambridge)
,
Benjamin
Ryskeldi-Falcon
(Medical Research Council Laboratory of Molecular Biology)
,
Alexey G.
Murzin
(Medical Research Council Laboratory of Molecular Biology)
,
Michel
Goedert
(Medical Research Council Laboratory of Molecular Biology)
,
Sjors H. W.
Scheres
(MRC Laboratory of Molecular Biology)
Co-authored by industrial partner:
No
Type:
Journal Paper
Journal:
Nature
State:
Published (Approved)
Published:
March 2022
Diamond Proposal Number(s):
17434
,
23268
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.
Journal Keywords: Cryoelectron microscopy; Molecular neuroscience
Subject Areas:
Biology and Bio-materials
Diamond Offline Facilities:
Electron Bio-Imaging Centre (eBIC)
Instruments:
Krios III-Titan Krios III at Diamond
Added On:
01/04/2022 08:22
Discipline Tags:
Neurodegenerative Diseases
Non-Communicable Diseases
Health & Wellbeing
Neurology
Structural biology
Life Sciences & Biotech
Technical Tags:
Microscopy
Electron Microscopy (EM)
Cryo Electron Microscopy (Cryo EM)