PXD055345 is an
original dataset announced via ProteomeXchange.
Dataset Summary
Title | Heteromeric amyloid filaments of ANXA11 and TDP-43 in FTLD-TDP Type C |
Description | Neurodegenerative diseases are characterised by the abnormal filamentous assembly of specific proteins in the central nervous system1. Human genetic studies 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 electron cryo- microscopy (cryo-EM) have enabled the structures of the protein filaments to be determined from patient brains1. 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 B3,4. 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. |
HostingRepository | PRIDE |
AnnounceDate | 2025-05-07 |
AnnouncementXML | Submission_2025-05-07_02:06:22.843.xml |
DigitalObjectIdentifier | |
ReviewLevel | Peer-reviewed dataset |
DatasetOrigin | Original dataset |
RepositorySupport | Unsupported dataset by repository |
PrimarySubmitter | Sew Peak-Chew |
SpeciesList | scientific name: Homo sapiens (Human); NCBI TaxID: 9606; |
ModificationList | deamidated residue |
Instrument | Q Exactive Plus |
Dataset History
Revision | Datetime | Status | ChangeLog Entry |
0 | 2024-08-29 04:02:05 | ID requested | |
⏵ 1 | 2025-05-07 02:06:23 | announced | |
Publication List
Arseni D, Nonaka T, Jacobsen MH, Murzin AG, Cracco L, Peak-Chew SY, Garringer HJ, Kawakami I, Suzuki H, Onaya M, Saito Y, Murayama S, Geula C, Vidal R, Newell KL, Mesulam M, Ghetti B, Hasegawa M, Ryskeldi-Falcon B, Heteromeric amyloid filaments of ANXA11 and TDP-43 in FTLD-TDP type C. Nature, 634(8034):662-668(2024) [pubmed] |
10.1038/s41586-024-08024-5; |
Keyword List
submitter keyword: frontotemporal dementia,Neurodegenerative disease, TDP-43 and TMEM106B |
Contact List
Benjamin Ryskeldi-Falcon |
contact affiliation | Medical Research Council Laboratory of Molecular Biology Francis Crick Avenue Cambridge Biomedical Campus Cambridge CB2 0QH |
contact email | bfalcon@mrc-lmb.cam.ac.uk |
lab head | |
Sew Peak-Chew |
contact affiliation | MRC-LMB |
contact email | spc@mrc-lmb.cam.ac.uk |
dataset submitter | |
Full Dataset Link List
Dataset FTP location
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PRIDE project URI |
Repository Record List
[ + ]
[ - ]
- PRIDE
- PXD055345
- Label: PRIDE project
- Name: Heteromeric amyloid filaments of ANXA11 and TDP-43 in FTLD-TDP Type C