<<< Full experiment listing

PXD044790-1

PXD044790 is an original dataset announced via ProteomeXchange.

Dataset Summary
TitleKnockout validation of Phospholipases in context of Batten disease Cln3
DescriptionBatten disease, the most prevalent form of neurodegeneration in children, is caused by mutations in the CLN3 gene, which encodes a lysosomal transmembrane protein. The loss of CLN3 leads to significant accumulation of glycerophosphodiesters (GPDs), the end products of glycerophospholipid catabolism in the lysosome. Despite GPD storage upon CLN3 loss being robustly detected across species, the role of GPDs in neuropathology remains unclear. Here, we demonstrate that GPDs act as potent inhibitors of glycerophospholipid catabolism in the lysosome. Mechanistically, we found that GPDs bind and competitively inhibit the lysosomal phospholipases PLA2G15 and PLBD2, which we establish to possess phospholipase B activity and the latter of which is identified in this study. Interestingly, GPDs show more potency in inhibiting the rate-limiting lysophospholipase activity of these lipases. Consistent with our biochemical data, loss of CLN3 and sequestration of GPDs lead to the accumulation of toxic lysophospholipids, intermediates in lipid degradation, in lysosomes of CLN3-deficient cells and tissues. This work provides novel insights into lysosomal phospholipid catabolism and establishes that the storage material in Batten disease directly disrupts lysosomal lipid homeostasis, suggesting GPD clearance as a potential therapeutic approach to this fatal disease.
HostingRepositoryMassIVE
AnnounceDate2024-02-23
AnnouncementXMLSubmission_2024-02-23_06:31:46.988.xml
DigitalObjectIdentifier
ReviewLevelNon peer-reviewed dataset
DatasetOriginOriginal dataset
RepositorySupportUnsupported dataset by repository
PrimarySubmitterLeibniz FLI Proteomics
SpeciesList scientific name: Homo sapiens; common name: human; NCBI TaxID: 9606;
ModificationListOxidation; Carbamidomethyl
InstrumentOrbitrap Exploris 480
Dataset History
RevisionDatetimeStatusChangeLog Entry
02023-08-23 05:14:19ID requested
12024-02-23 06:31:47announced
Publication List
no publication
Keyword List
submitter keyword: Batten disease, glycerophosphodiesters, GPD, CLN3, lysosome
Contact List
Alessandro Ori
contact affiliationLeibniz Institute on Aging Fritz Lipmann Institute (FLI)
contact emailalessandro.ori@leibniz-fli.de
lab head
Leibniz FLI Proteomics
contact affiliationLeibniz FLI
contact emailproteomics@leibniz-fli.de
dataset submitter
Full Dataset Link List
MassIVE dataset URI
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://massive.ucsd.edu/v06/MSV000092729/