PXD037107 is an
original dataset announced via ProteomeXchange.
Dataset Summary
Title | Nucleocytoplasmic mRNA redistribution accompanies RNA binding protein mislocalisation in ALS motor neurons and is restored by VCP inhibition |
Description | Although the pathological hallmark of amyotrophic lateral sclerosis (ALS) is the nucleocytoplasmic mislocalisation of RNA binding proteins (RBPs), such as TDP-43 and FUS, the nucleocytoplasmic distribution of mRNA remains uncharacterised. Here, we used subcellular fractionation with RNA sequencing and proteomics to assess nucleocytoplasmic mRNA and protein localisation in human induced pluripotent stem cell-derived motor neurons (iPSNs) from ALS patients with TARDBP mutations, VCP mutations, and controls with VCP mutations knocked-in with CRISPR/Cas9. In each mutant group, we found substantial nucleocytoplasmic mRNA redistribution, particularly in transcripts involved in protein binding. Redistributed transcripts in ALS iPSNs were enriched in protein-coding biotypes, exhibited longer lengths, and had enhanced interactions with RBPs, including TDP-43 and FUS. Using mass spectrometry in TARDBP mutant, VCP mutant, and VCP mutant knock-in iPSNs, we reveal widespread protein mislocalisation, especially in RBPs. We find that mislocalised proteins exhibit substantially greater binding to redistributed transcripts than non-redistributed mRNAs, suggesting that RBP mislocalisation may be directly coupled to mRNA redistribution. Remarkably, treatment with the VCP D2 ATPase domain inhibitor ML240 restored both nucleocytoplasmic mRNA redistribution and protein mislocalisation not only in VCP mutants but also in TARDBP mutant iPSNs. Functional assays in VCP mutant iPSNs further confirmed that ML240 restores lysosomal localisation from the perinuclear region towards the neurites and reduces oxidative stress. Our findings demonstrate that ALS motor neurons exhibit concomitant nucleocytoplasmic mRNA redistribution and RBP |
HostingRepository | PRIDE |
AnnounceDate | 2024-10-22 |
AnnouncementXML | Submission_2024-10-22_06:05:53.162.xml |
DigitalObjectIdentifier | |
ReviewLevel | Peer-reviewed dataset |
DatasetOrigin | Original dataset |
RepositorySupport | Unsupported dataset by repository |
PrimarySubmitter | Mark Skehel |
SpeciesList | scientific name: Homo sapiens (Human); NCBI TaxID: 9606; |
ModificationList | No PTMs are included in the dataset |
Instrument | Orbitrap Fusion Lumos |
Dataset History
Revision | Datetime | Status | ChangeLog Entry |
0 | 2022-09-30 04:03:15 | ID requested | |
1 | 2023-10-13 12:20:39 | announced | |
2 | 2023-11-14 09:06:03 | announced | 2023-11-14: Updated project metadata. |
⏵ 3 | 2024-10-22 06:05:54 | announced | 2024-10-22: Updated project metadata. |
Publication List
10.1016/j.neuron.2023.06.019; |
Ziff OJ, Harley J, Wang Y, Neeves J, Tyzack G, Ibrahim F, Skehel M, Chakrabarti AM, Kelly G, Patani R, Nucleocytoplasmic mRNA redistribution accompanies RNA binding protein mislocalization in ALS motor neurons and is restored by VCP ATPase inhibition. Neuron, 111(19):3011-3027.e7(2023) [pubmed] |
Keyword List
submitter keyword: Human, iPSC, ALS, motor neuron, lc-ms/ms |
Contact List
Rickie Patani |
contact affiliation | The Francis Crick Institute, London, UK Department of Neuromuscular Diseases, University College Londodn, UK National Hospital for Neurology and Neurosurgery, UCL NHS Foundation Trust, Londodn, UK |
contact email | rickie.patani@ucl.ac.uk |
lab head | |
Mark Skehel |
contact affiliation | Francis Crick Institute |
contact email | skehelm@crick.ac.uk |
dataset submitter | |
Full Dataset Link List
Dataset FTP location
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PRIDE project URI |
Repository Record List
[ + ]
[ - ]
- PRIDE
- PXD037107
- Label: PRIDE project
- Name: Nucleocytoplasmic mRNA redistribution accompanies RNA binding protein mislocalisation in ALS motor neurons and is restored by VCP inhibition