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

Diana Arseni, Takashi Nonaka, Max H. Jacobsen, Alexey G. Murzin, Laura Cracco, Sew Y. Peak-Chew, Holly J. Garringer, Ito Kawakami, Hisaomi Suzuki, Misumoto Onaya, Yuko Saito, Shigeo Murayama, Changiz Geula, Ruben Vidal, Kathy L. Newell, Marsel Mesulam, Bernardino Ghetti, Masato Hasegawa and Benjamin Ryskeldi-Falcon ()
Additional contact information
Diana Arseni: MRC Laboratory of Molecular Biology
Takashi Nonaka: Tokyo Metropolitan Institute of Medical Science
Max H. Jacobsen: Indiana University School of Medicine
Alexey G. Murzin: MRC Laboratory of Molecular Biology
Laura Cracco: Indiana University School of Medicine
Sew Y. Peak-Chew: MRC Laboratory of Molecular Biology
Holly J. Garringer: Indiana University School of Medicine
Ito Kawakami: Tokyo Metropolitan Institute of Medical Science
Hisaomi Suzuki: National Hospital Organization Shimofusa Psychiatric Center
Misumoto Onaya: National Hospital Organization Shimofusa Psychiatric Center
Yuko Saito: Tokyo Metropolitan Institute for Geriatrics and Gerontology
Shigeo Murayama: Tokyo Metropolitan Institute for Geriatrics and Gerontology
Changiz Geula: Northwestern University
Ruben Vidal: Indiana University School of Medicine
Kathy L. Newell: Indiana University School of Medicine
Marsel Mesulam: Northwestern University
Bernardino Ghetti: Indiana University School of Medicine
Masato Hasegawa: Tokyo Metropolitan Institute of Medical Science
Benjamin Ryskeldi-Falcon: MRC Laboratory of Molecular Biology

Nature, 2024, vol. 634, issue 8034, 662-668

Abstract: 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.

Date: 2024
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41586-024-08024-5 Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:634:y:2024:i:8034:d:10.1038_s41586-024-08024-5

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/s41586-024-08024-5

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().