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

Ryskeldi-Falcon, Benjamin
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Nature ( 2024 ) Cite this article

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Abstract

Neurodegenerative diseases are characterised by the abnormal filamentous assembly of specific proteins in the central nervous system 1 . Human genetic studies established a causal role for protein assembly in neurodegeneration 2 . However, the underlying molecular mechanisms remain largely unknown, which is limiting progress in developing clinical tools for these diseases. Recent advances in electron cryo-microscopy (cryo-EM) have enabled the structures of the protein filaments to be determined from patient brains 1 . All diseases studied to date have been characterised 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 B 3,4 . Here, we used cryo-EM 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 G282/284–N345 and ANXA11 residues L39–Y74 from their respective low-complexity domains (LCDs). Regions of TDP-43 and ANXA11 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 a ~22 kDa N-terminal fragment (NTF) lacking the annexin core domain. Immunohistochemistry of brain sections showed the co-localisation 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 human brain revises our understanding of amyloid assembly and may be of significance for the pathogenesis of neurodegenerative diseases.

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Authors and Affiliations

  1. MRC Laboratory of Molecular Biology, Cambridge, UK

    Diana Arseni, Alexey G. Murzin, Sew Y. Peak-Chew & Benjamin Ryskeldi-Falcon

  2. Department of Brain and Neurosciences, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan

    Takashi Nonaka, Ito Kawakami & Masato Hasegawa

  3. Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA

    Max H. Jacobsen, Laura Cracco, Holly J. Garringer, Ruben Vidal, Kathy L. Newell & Bernardino Ghetti

  4. Department of Psychiatry, National Hospital Organization Shimofusa Psychiatric Center, Chiba, Japan

    Hisaomi Suzuki & Misumoto Onaya

  5. Department of Neuropathology, Tokyo Metropolitan Institute for Geriatrics and Gerontology, Tokyo, Japan

    Yuko Saito & Shigeo Murayama

  6. Mesulam Center for Cognitive Neurology and Alzheimer’s Disease, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA

    Changiz Geula & Marsel Mesulam

Authors

  1. Diana Arseni

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  2. Takashi Nonaka

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  3. Max H. Jacobsen

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  4. Alexey G. Murzin

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  5. Laura Cracco

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  6. Sew Y. Peak-Chew

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  7. Holly J. Garringer

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  8. Ito Kawakami

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  9. Hisaomi Suzuki

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  10. Misumoto Onaya

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  11. Yuko Saito

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  12. Shigeo Murayama

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  13. Changiz Geula

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  14. Ruben Vidal

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  15. Kathy L. Newell

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  16. Marsel Mesulam

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  17. Bernardino Ghetti

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  18. Masato Hasegawa

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  19. Benjamin Ryskeldi-Falcon

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Corresponding author

Correspondence to Benjamin Ryskeldi-Falcon .

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Arseni, D., Nonaka, T., Jacobsen, M.H. et al. Heteromeric amyloid filaments of ANXA11 and TDP-43 in FTLD-TDP Type C. Nature (2024). https://doi.org/10.1038/s41586-024-08024-5

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  • DOI : https://doi.org/10.1038/s41586-024-08024-5

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