PXD055345

PXD055345 is an original dataset announced via ProteomeXchange.

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

Revision	Datetime	Status	ChangeLog Entry
0	2024-08-29 04:02:05	ID requested
⏵ 1	2025-05-07 02:06:23	announced

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;

submitter keyword: frontotemporal dementia,Neurodegenerative disease, TDP-43 and TMEM106B

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

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2025/05/PXD055345

PRIDE project URI

• PRIDE
  1. PXD055345
     1. Label: PRIDE project
     2. Name: Heteromeric amyloid filaments of ANXA11 and TDP-43 in FTLD-TDP Type C