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 Lashley, Tamas Revesz, Gabor G. Kovacs, John Swieten, Masaki Takao, Masato Hasegawa, Bernardino Ghetti, Maria Grazia Spillantini, Benjamin Ryskeldi-Falcon, Alexey G. Murzin, Michel Goedert () and Sjors H. W. Scheres ()
Additional contact information
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 Lövestam: 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. Hallinan: 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, National Center of Neurology and Psychiatry
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
John Swieten: Erasmus Medical Centre
Masaki Takao: National Center of Neurology and Psychiatry, National Center 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: Medical Research Council Laboratory of Molecular Biology

Nature, 2022, vol. 605, issue 7909, 310-314

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41586-022-04650-z

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