PXD047571-1

PXD047571 is an original dataset announced via ProteomeXchange.

Title	Insights from multi-omic modelling of neurodegeneration in Xeroderma Pigmentosum using an induced pluripotent stem cell system
Description	Xeroderma pigmentosum (XP) is caused by defective nucleotide excision-repair of DNA damage. This results in hypersensitivity to ultraviolet light and increased skin cancer risk, as sunlight-induced photoproducts remain unrepaired. However, many XP patients also display early-onset neurodegeneration, which leads to premature death. The mechanism of neurodegeneration is unknown. Here, we investigate XP neurodegeneration using pluripotent stem cells derived from XP patients and healthy relatives, performing functional multi-omics on samples during neuronal differentiation. We show substantially increased levels of 5',8-cyclopurine and 8-oxopurine in XP neuronal DNA secondary to marked oxidative stress. Furthermore, we find that the endoplasmic reticulum stress response is upregulated and reversal of the mutant genotype is associated with phenotypic rescue. Critically, XP neurons exhibit inappropriate downregulation of the protein clearance ubiquitin-proteasome system (UPS). Chemical enhancement of UPS activity in XP neuronal models improves phenotypes, albeit inadequately. Although more work is required, this study presents insights with intervention potential.
HostingRepository	PRIDE
AnnounceDate	2024-04-18
AnnouncementXML	Submission_2024-04-18_03:44:56.692.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Graeme Benstead-Hume
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2023-12-06 04:16:56	ID requested
⏵ 1	2024-04-18 03:44:57	announced
2	2024-10-22 06:36:33	announced	2024-10-22: Updated project metadata.

Dataset with its publication pending

submitter keyword: iPSCs,Xeroderma Pigmentosum, XP, Neurodegeneration, Ubiquitin Proteasome System (UPS), DNA damage, Oxidative stress, Endoplasmic Reticulum stress response, Early detection.

Jyoti Choudhary
contact affiliation	Functional Proteomics, Institute of Cancer Research
contact email	jyoti.choudhary@icr.ac.uk
lab head
Graeme Benstead-Hume
contact affiliation	ICR
contact email	ghume@icr.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/2024/04/PXD047571

PRIDE project URI

• PRIDE
  1. PXD047571
     1. Label: PRIDE project
     2. Name: Insights from multi-omic modelling of neurodegeneration in Xeroderma Pigmentosum using an induced pluripotent stem cell system