PXD044821-1

PXD044821 is an original dataset announced via ProteomeXchange.

Title	TAF15 amyloid filaments in neurodegenerative disease
Description	Frontotemporal dementia (FTD) is the most common form of dementia after Alzheimer's disease and results from frontotemporal lobar degeneration (FTLD). The pathological hallmarks of FTLD are neuronal inclusions of specific, abnormally assembled proteins1. In the majority of cases, the inclusions contain amyloid filament assemblies of TAR DNA-binding protein 43 (TDP-43) or tau, with distinct filament structures characterising different FTLD subtypes2,3. The presence, identities and structures of amyloid filaments in the remaining ~10% of FTLD cases are unknown, but are widely believed to be composed of the protein fused in sarcoma (FUS). As such, these cases are commonly referred to as FTLD-FUS. Here, we used cryogenic electron microscopy (cryo-EM) to determine the structures of amyloid filaments extracted from the prefrontal and temporal cortices of four individuals with FTLD-FUS. Unexpectedly, we found abundant amyloid filaments of the FUS homologue TATA-binding protein-associated factor 15 (TAF15), rather than of FUS itself. The filament fold is formed from residues 7 to 99 in the low-complexity domain (LCD) of TAF15 and was identical between individuals. The formation of TAF15 amyloid filaments with a characteristic fold in FTLD establishes TAF15 proteinopathy in neurodegenerative disease. Furthermore, we found TAF15 filaments with the same fold in the motor cortex and brainstem of two of the individuals, who also showed changes associated with amyotrophic lateral sclerosis (ALS), suggesting that TAF15 proteinopathy may underlie a disease spectrum of FTLD and ALS. The structure of TAF15 amyloid filaments provides a basis for the development of model systems of neurodegenerative disease, as well as for the design of diagnostic and therapeutic tools targeting TAF15 proteinopathy.
HostingRepository	PRIDE
AnnounceDate	2023-12-07
AnnouncementXML	Submission_2023-12-07_00:47:21.940.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	No PTMs are included in the dataset
Instrument	Q Exactive HF

Revision	Datetime	Status	ChangeLog Entry
0	2023-08-24 00:40:56	ID requested
⏵ 1	2023-12-07 00:47:22	announced

10.1038/S41586-023-06801-2;

submitter keyword: Neurodegeneration Frontotemporal dementia Frontotemporal lobar degeneration FTLD-FET

Benjamin Ryskeldi-Falcon
contact affiliation	MRC Laboratory of Molecular Biology, Neurobiology division, Cambridge, UK
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

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PRIDE project URI

• PRIDE
  1. PXD044821
     1. Label: PRIDE project
     2. Name: TAF15 amyloid filaments in neurodegenerative disease