PXD031083-1

PXD031083 is an original dataset announced via ProteomeXchange.

Title	Gel-like inclusions of C-terminal fragments of TDP-43 sequester stalled proteasomes in neurons
Description	Aggregation of the multifunctional RNA-binding protein TDP-43 defines large subgroups of amyotrophic lateral sclerosis and frontotemporal dementia and correlates with neurodegeneration in both diseases. In disease, characteristic C-terminal fragments of ~25 kDa ("TDP-25") accumulate in cytoplasmic inclusions. Here, we analyzed gain-of-function mechanisms of TDP-25 combining cryo-electron tomography, proteomics and functional assays. In neurons, cytoplasmic TDP-25 inclusions are amorphous and photobleaching experiments revealed gel-like biophysical properties far less dynamic than nuclear TDP-43. Compared to full length TDP-43, the TDP-25 interactome was depleted of lowcomplexity domain proteins. TDP-25 inclusions are enriched in 26S proteasomes adopting exclusively substrate-processing conformations, suggesting that inclusions sequester proteasomes, which are largely stalled and no longer undergo the cyclic conformational changes required for proteolytic activity. Reporter assays confirmed that TDP-25 impaired proteostasis, which is further enhanced by ALS-causing mutations. These findings bolster the importance of proteasome dysfunction in ALS/FTD. Key words ALS / neurodegeneration / phase separation / proteasome / TDP-43 Introduction
HostingRepository	PRIDE
AnnounceDate	2022-05-08
AnnouncementXML	Submission_2022-05-08_03:25:25.144.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Mario Oroshi
SpeciesList	scientific name: Rattus norvegicus (Rat); NCBI TaxID: 10116;
ModificationList	acetylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Exploris 480

Revision	Datetime	Status	ChangeLog Entry
0	2022-01-19 08:02:07	ID requested
⏵ 1	2022-05-08 03:25:25	announced

Dataset with its publication pending

submitter keyword: ALS / neurodegeneration / phase separation / proteasome / TDP-43

Matthias Mann
contact affiliation	Max Planck Institute of Biochemistry, Martinsried, Germany
contact email	mmann@biochem.mpg.de
lab head
Mario Oroshi
contact affiliation	Proteomics
contact email	oroshi@biochem.mpg.de
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD031083
     1. Label: PRIDE project
     2. Name: Gel-like inclusions of C-terminal fragments of TDP-43 sequester stalled proteasomes in neurons