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)