PXD003140

PXD003140 is an original dataset announced via ProteomeXchange.

Title	Hypomorphic mutations in PLAA cause an infantile neurodevelopmental syndrome by disrupting synaptic protein turnover through multivesicular body dysfunction
Description	During endosomal trafficking, the ubiquitin-status of membrane-bound protein cargo determines whether it is recycling to the surface or trafficked through intermediate multivesicular bodies (MVBs) for lysosomal degradation. Neurons, particularly their synapses, are extremely sensitive to perturbations in endolysosomal transport. We describe a lethal severe neurodevelopmental disorder (characterised by limb hypertonia, central hypotonia, progressive spasticity, seizures, secondary microcephaly and no developmental progress) in seven infants from three kindreds with a homozygous G23V PLAA mutation. PLAA is an ubiquitiously expressed and highly conserved ubiquitin-binding adaptor protein implicated in proteostasis. A mouse Plaa knockout was embyonically lethal but using CRISPR gene editing we recreated an allelic G23V series of Plaa mouse mutants leading to early onset neural dysfunction and death. Unlike in yeast, mammalian Plaa mutant cells do not globally affect free ubiquitin homeostasis but show defects in the capture and processing of ubiquitinated-membrane cargo for concentration into functional MVBs disrupting basal macroautophagy.
HostingRepository	PRIDE
AnnounceDate	2018-07-11
AnnouncementXML	Submission_2018-07-11_07:52:05.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Alex von kriegsheim
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	No PTMs are included in the dataset
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2015-11-03 07:04:13	ID requested
⏵ 1	2018-07-11 07:52:06	announced

Dataset with its publication pending

curator keyword: Biomedical

submitter keyword: Mouse cerebelluym

Alex von Kriegsheim
contact affiliation	IGMM, University of Edinburgh
contact email	kriegsheim@gmail.com
lab head
Alex von kriegsheim
contact affiliation	Systems Biology
contact email	alex.vonkriegsheim@ucd.ie
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/2018/07/PXD003140

PRIDE project URI

• PRIDE
  1. PXD003140
     1. Label: PRIDE project
     2. Name: Hypomorphic mutations in PLAA cause an infantile neurodevelopmental syndrome by disrupting synaptic protein turnover through multivesicular body dysfunction