Abstract
Neurodegenerative diseases are characterized by the abnormal filamentous assembly of specific proteins in the central nervous system1. Human genetic studies have established a causal role for protein assembly in neurodegeneration2. However, the underlying molecular mechanisms remain largely unknown, which is limiting progress in developing clinical tools for these diseases. Recent advances in cryo-electron microscopy have enabled the structures of the protein filaments to be determined from the brains of patients1. All neurodegenerative diseases studied to date have been characterized by the self-assembly of proteins in homomeric amyloid filaments, including that of TAR DNA-binding protein 43 (TDP-43) in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) types A and B3,4. Here we used cryo-electron microscopy to determine filament structures from the brains of individuals with FTLD-TDP type C, one of the most common forms of sporadic FTLD-TDP. Unexpectedly, the structures revealed that a second protein, annexin A11 (ANXA11), co-assembles with TDP-43 in heteromeric amyloid filaments. The ordered filament fold is formed by TDP-43 residues G282/G284–N345 and ANXA11 residues L39–Y74 from their respective low-complexity domains. Regions of TDP-43 and ANXA11 that were previously implicated in protein–protein interactions form an extensive hydrophobic interface at the centre of the filament fold. Immunoblots of the filaments revealed that the majority of ANXA11 exists as an approximately 22 kDa N-terminal fragment lacking the annexin core domain. Immunohistochemistry of brain sections showed the colocalization of ANXA11 and TDP-43 in inclusions, redefining the histopathology of FTLD-TDP type C. This work establishes a central role for ANXA11 in FTLD-TDP type C. The unprecedented formation of heteromeric amyloid filaments in the human brain revises our understanding of amyloid assembly and may be of significance for the pathogenesis of neurodegenerative diseases.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 662-668 |
| Number of pages | 7 |
| Journal | Nature |
| Volume | 634 |
| Issue number | 8034 |
| DOIs | |
| State | Published - Oct 17 2024 |
Funding
We thank the individuals and their families for donating brain tissue; the Brain Library of the Dementia Laboratory at Indiana University School of Medicine for supplying tissue from individuals 2, 5 and 6 with FTLD-TDP type C, individuals 1 and 2 with FTLD-TDP type A and individuals 1 and 2 with FTLD-TDP type B; the Alzheimer\u2019s Disease Research Center at the Mesulam Center for Cognitive Neurology and Alzheimer\u2019s Disease, Feinberg School of Medicine, Northwestern University for supplying tissue from individuals 7\u20139 with FTLD-TDP type C; the Indiana University School of Medicine Center for Electron Microscopy (iCEM) for support with immuno-EM; the Indiana University School of Medicine Center for Medical Genomics for next-generation DNA sequencing; E. Doud for help with mass spectrometry; the staff at the MRC Laboratory of Molecular Biology Electron Microscopy Facility for access to and support with cryo-EM; the staff at the MRC Laboratory of Molecular Biology Scientific Computing Facility for access to and support with computing; and T. Behr, A. Bertolotti, R. Chen, R. A. Crowther,\u00A0S. W. Davies, A. Giblin, M. Goedert, S. H. W. Scheres, S. Tetter and N. Varghese for discussions. This work was supported by the Medical Research Council, as part of UK Research and Innovation (MC_UP_1201/25 to B.R.-F.); the Hans Und Ilse Breuer Stiftung (to B.R.-F.); the US National Institutes of Health (R01NS137469 to K.L.N., L.C. and B.R.-F.; P30AG072977, R01AG077444, R01DC008552, P30AG13854, R01AG056258 and R01NS085770 to C.G. and M.M.; and R01-NS110437, RF1-AG071177 and R01-AG080001 to R.V. and B.G); the Japan Agency for Medical Research and Development (AMED; JP20dm0207072 to M.H. and JP21wm0425019 to Y.S. and S.M.); the Japan Science and Technology Agency (JST) Core Research for Evolutional Science and Technology (CREST; JPMJCR18H3 to M.H.); the Japan Society for the Promotion of Science (JSPS) KAKENHI (JP22H04923 (CoBiA) to Y.S. and S.M.); the Integrated Research Initiative for Living Well with Dementia (IRIDE) of the Tokyo Metropolitan Institute for Geriatrics and Gerontology IRIDE (to Y.S. and S.M.); and The Leverhulme Trust (ECF-2022-610 to D.A.). For the purpose of open access, the MRC Laboratory of Molecular Biology has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising. We thank the individuals and their families for donating brain tissue; the Brain Library of the Dementia Laboratory at Indiana University School of Medicine for supplying tissue from individuals 2, 5 and 6 with FTLD-TDP type C, individuals 1 and 2 with FTLD-TDP type A and individuals 1 and 2 with FTLD-TDP type B; the Alzheimer\u2019s Disease Research Center at the Mesulam Center for Cognitive Neurology and Alzheimer\u2019s Disease, Feinberg School of Medicine, Northwestern University for supplying tissue from individuals 7\u20139 with FTLD-TDP type C; the Indiana University School of Medicine Center for Electron Microscopy (iCEM) for support with immuno-EM; the Indiana University School of Medicine Center for Medical Genomics for next-generation DNA sequencing; E. Doud for help with mass spectrometry; the staff at the MRC Laboratory of Molecular Biology Electron Microscopy Facility for access to and support with cryo-EM; the staff at the MRC Laboratory of Molecular Biology Scientific Computing Facility for access to and support with computing; and T. Behr, A. Bertolotti, R. Chen, R. A. Crowther, S. W. Davies, A. Giblin, M. Goedert, S. H. W. Scheres, S. Tetter and N. Varghese for discussions. This work was supported by the Medical Research Council, as part of UK Research and Innovation (MC_UP_1201/25 to B.R.-F.); the Hans Und Ilse Breuer Stiftung (to B.R.-F.); the US National Institutes of Health (R01NS137469 to K.L.N., L.C. and B.R.-F.; P30AG072977, R01AG077444, R01DC008552, P30AG13854, R01AG056258 and R01NS085770 to C.G. and M.M.; and R01-NS110437, RF1-AG071177 and R01-AG080001 to R.V. and B.G); the Japan Agency for Medical Research and Development (AMED; JP20dm0207072 to M.H. and JP21wm0425019 to Y.S. and S.M.); the Japan Science and Technology Agency (JST) Core Research for Evolutional Science and Technology (CREST; JPMJCR18H3 to M.H.); the Japan Society for the Promotion of Science (JSPS) KAKENHI (JP22H04923 (CoBiA) to Y.S. and S.M.); the Integrated Research Initiative for Living Well with Dementia (IRIDE) of the Tokyo Metropolitan Institute for Geriatrics and Gerontology IRIDE (to Y.S. and S.M.); and The Leverhulme Trust (ECF-2022-610 to D.A.). For the purpose of open access, the MRC Laboratory of Molecular Biology has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising.
ASJC Scopus subject areas
- General