Heteromeric amyloid filaments of ANXA11 and TDP-43 in FTLD-TDP type C

dc.contributor.authorArseni, Diana
dc.contributor.authorNonaka, Takashi
dc.contributor.authorJacobsen, Max H.
dc.contributor.authorMurzin, Alexey G.
dc.contributor.authorCracco, Laura
dc.contributor.authorPeak-Chew, Sew Y.
dc.contributor.authorGarringer, Holly J.
dc.contributor.authorKawakami, Ito
dc.contributor.authorSuzuki, Hisaomi
dc.contributor.authorOnaya, Misumoto
dc.contributor.authorSaito, Yuko
dc.contributor.authorMurayama, Shigeo
dc.contributor.authorGeula, Changiz
dc.contributor.authorVidal, Ruben
dc.contributor.authorNewell, Kathy L.
dc.contributor.authorMesulam, Marsel
dc.contributor.authorGhetti, Bernardino
dc.contributor.authorHasegawa, Masato
dc.contributor.authorRyskeldi-Falcon, Benjamin
dc.contributor.departmentPathology and Laboratory Medicine, School of Medicine
dc.date.accessioned2024-11-13T13:54:26Z
dc.date.available2024-11-13T13:54:26Z
dc.date.issued2024
dc.description.abstractNeurodegenerative 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.
dc.eprint.versionFinal published version
dc.identifier.citationArseni D, Nonaka T, Jacobsen MH, et al. Heteromeric amyloid filaments of ANXA11 and TDP-43 in FTLD-TDP type C. Nature. 2024;634(8034):662-668. doi:10.1038/s41586-024-08024-5
dc.identifier.urihttps://hdl.handle.net/1805/44545
dc.language.isoen_US
dc.publisherSpringer Nature
dc.relation.isversionof10.1038/s41586-024-08024-5
dc.relation.journalNature
dc.rightsAttribution 4.0 Internationalen
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.sourcePMC
dc.subjectAmyloid
dc.subjectAnnexins
dc.subjectAphasia
dc.subjectBrain
dc.subjectFrontotemporal dementia
dc.titleHeteromeric amyloid filaments of ANXA11 and TDP-43 in FTLD-TDP type C
dc.typeArticle
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