PXD045041

PXD045041 is an original dataset announced via ProteomeXchange.

Title	Proteomic dissection of Vanishing white matter pathogenesis
Description	Vanishing white matter (VWM) is a leukodystrophy caused by biallelic pathogenic variants in eukaryotic translation initiation factor 2B. Neuropathology includes lack of reactive gliosis, paucity of myelin, and axonal abnormalities. Alteration in proteins involved in cellular metabolism has also been implicated in the disease. It, however, remains unclear which factors contribute to VWM pathogenesis. Here, we aimed at gaining insight into the basis of VWM pathogenesis using the 2b5ho mouse model of VWM. We first investigated the temporal proteome in the cerebellum, corpus callosum, cortex, and brainstem of 2b5ho and wild type (WT) mice. Protein changes observed in 2b5ho mice were then cross-referenced with published proteomic datasets from post mortem VWM patient brain tissue to define alterations relevant to the human disease. By comparing 2b5ho mice with their region- and age-matched WT counterparts, we identified region-specific protein changes associated with disease development and progression. We showed that the proteome in the cerebellum and cortex of 2b5ho mice was already deregulated prior to pathology development, whereas proteome changes in the corpus callosum only occurred after onset of pathology. Remarkably, protein changes in the brainstem were transient, indicating that a compensatory mechanism might occur in this region throughout the disease course. Gene ontology overrepresentation analysis revealed that proteome changes observed in 2b5ho mouse brains reflect alterations in features well-known in VWM. Side-by-side comparison of the 2b5ho mouse and VWM patient brain proteomes revealed that part of protein changes were the same as in VWM patients. These could represent relevant changes that contribute to the disease or even drive its progression in VWM patients. Taken together, we show that the proteome in the brain of 2b5ho mice is affected in a region-specific and time-dependent manner. We found that the 2b5ho mouse model partly replicates the human disease at the protein level, and provides a spatiotemporal proteome resource to study aspects of VWM pathogenesis. This resource highlights alterations presenting from early to late disease stages, and those that possibly drive disease progression.
HostingRepository	PRIDE
AnnounceDate	2024-06-16
AnnouncementXML	Submission_2024-06-15_23:04:41.126.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Jodie Man
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	acetylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Q Exactive HF

Revision	Datetime	Status	ChangeLog Entry
0	2023-09-01 10:21:42	ID requested
⏵ 1	2024-06-15 23:04:41	announced

Man JHK, Zarekiani P, Mosen P, de Kok M, Debets DO, Breur M, Altelaar M, van der Knaap MS, Bugiani M, Proteomic dissection of vanishing white matter pathogenesis. Cell Mol Life Sci, 81(1):234(2024) [pubmed]

10.1007/s00018-024-05258-4;

submitter keyword: Quantitative proteomics, Brain, Leukodystrophy,Vanishing white matter, Disease progression

Marianna Bugiani
contact affiliation	Department of Pathology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
contact email	m.bugiani@amsterdamumc.nl
lab head
Jodie Man
contact affiliation	Amsterdam UMC - Location VUMc
contact email	j.man@amsterdamumc.nl
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/2024/06/PXD045041

PRIDE project URI

• PRIDE
  1. PXD045041
     1. Label: PRIDE project
     2. Name: Proteomic dissection of Vanishing white matter pathogenesis