PXD031083 is an
original dataset announced via ProteomeXchange.
Dataset Summary
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 |
Dataset History
Revision | Datetime | Status | ChangeLog Entry |
0 | 2022-01-19 08:02:07 | ID requested | |
⏵ 1 | 2022-05-08 03:25:25 | announced | |
Publication List
Dataset with its publication pending |
Keyword List
submitter keyword: ALS / neurodegeneration / phase separation / proteasome / TDP-43 |
Contact List
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 | |
Full Dataset Link List
Dataset FTP location
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PRIDE project URI |
Repository Record List
[ + ]
[ - ]
- PRIDE
- PXD031083
- Label: PRIDE project
- Name: Gel-like inclusions of C-terminal fragments of TDP-43 sequester stalled proteasomes in neurons