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

73 Citations (Scopus)
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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

Funding Information:
We thank the patients’ families for donating brain tissues; U. Kuederli, M. Jacobsen, F. Epperson and R. M. Richardson for human brain collection and technical support; E. Gelpi for preparing brain samples from the ARTAG case; T. Darling and J. Grimmett for help with high-performance computing; M. Arai, T. Katsinelos and N. Obata for help with genotyping; I. Lavenir and J. A. Macdonald for helpful discussions; the EM facility of the Medical Research Council (MRC) Laboratory of Molecular Biology for help with cryo-EM data acquisition; the Edinburgh Brain and Tissue Bank, which is supported by the MRC, for providing brain samples of controls with normal neurology. We acknowledge Diamond Light Source for access and support of the cryo-EM facilities at the UK’s national Electron Bio-imaging Centre (under proposals EM17434-75 and BI23268-49), funded by the Wellcome Trust, MRC and BBSRC. This work was supported by the MRC (MC_UP_120/25 to B.R.-F., MC_U105184291 to M.G., and MC_UP_A025_1013 to S.H.W.S.), the EU/EFPIA/Innovative Medicines Initiative [2] Joint Undertaking IMPRiND (project 116060, to M.G. and M.G.S.), the Japan Agency for Science and Technology (Crest, JPMJCR18H3, to M. Hasegawa.), the Japan Agency for Medical Research and Development (AMED, JP20dm0207072, to M. Hasegawa., and AMED, JP21wm0425019, to M.T.), the Japan Society for the Promotion of Science (JSPS, Kakenhi 21K06417, to M.T.), the US National Institutes of Health (P30-AG010133, UO1-NS110437 and RF1-AG071177, to R.V. and B.G.) and the Department of Pathology and Laboratory Medicine, Indiana University School of Medicine (to R.V., K.L.N. and B.G.). M.G.S. was supported by the NIHR Cambridge Biomedical Research Centre. G.G.K. was supported by the Safra Foundation and the Rossy Foundation. T.R. was supported by the National Institute for Health Research Queen Square Biomedical Research Unit in Dementia. M.T. was supported by intramural funds from the National Center of Neurology and Psychiatry. T.L. holds an Alzheimer’s Research UK Senior Fellowship. The Queen Square Brain Bank is supported by the Reta Lila Weston Institute for Neurological Studies. For the purpose of Open Access, the authors have applied a CC-BY public copyright licence to any author accepted manuscript version arising from this submission.

Funding Information:
We thank the patients’ families for donating brain tissues; U. Kuederli, M. Jacobsen, F. Epperson and R. M. Richardson for human brain collection and technical support; E. Gelpi for preparing brain samples from the ARTAG case; T. Darling and J. Grimmett for help with high-performance computing; M. Arai, T. Katsinelos and N. Obata for help with genotyping; I. Lavenir and J. A. Macdonald for helpful discussions; the EM facility of the Medical Research Council (MRC) Laboratory of Molecular Biology for help with cryo-EM data acquisition; the Edinburgh Brain and Tissue Bank, which is supported by the MRC, for providing brain samples of controls with normal neurology. We acknowledge Diamond Light Source for access and support of the cryo-EM facilities at the UK’s national Electron Bio-imaging Centre (under proposals EM17434-75 and BI23268-49), funded by the Wellcome Trust, MRC and BBSRC. This work was supported by the MRC (MC_UP_120/25 to B.R.-F., MC_U105184291 to M.G., and MC_UP_A025_1013 to S.H.W.S.), the EU/EFPIA/Innovative Medicines Initiative [2] Joint Undertaking IMPRiND (project 116060, to M.G. and M.G.S.), the Japan Agency for Science and Technology (Crest, JPMJCR18H3, to M. Hasegawa.), the Japan Agency for Medical Research and Development (AMED, JP20dm0207072, to M. Hasegawa., and AMED, JP21wm0425019, to M.T.), the Japan Society for the Promotion of Science (JSPS, Kakenhi 21K06417, to M.T.), the US National Institutes of Health (P30-AG010133, UO1-NS110437 and RF1-AG071177, to R.V. and B.G.) and the Department of Pathology and Laboratory Medicine, Indiana University School of Medicine (to R.V., K.L.N. and B.G.). M.G.S. was supported by the NIHR Cambridge Biomedical Research Centre. G.G.K. was supported by the Safra Foundation and the Rossy Foundation. T.R. was supported by the National Institute for Health Research Queen Square Biomedical Research Unit in Dementia. M.T. was supported by intramural funds from the National Center of Neurology and Psychiatry. T.L. holds an Alzheimer’s Research UK Senior Fellowship. The Queen Square Brain Bank is supported by the Reta Lila Weston Institute for Neurological Studies. For the purpose of Open Access, the authors have applied a CC-BY public copyright licence to any author accepted manuscript version arising from this submission.

Publisher Copyright:
© 2022, The Author(s).

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