PXD044790

PXD044790 is an original dataset announced via ProteomeXchange.

Title	Knockout validation of Phospholipases in context of Batten disease Cln3
Description	Batten 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.
HostingRepository	MassIVE
AnnounceDate	2024-02-23
AnnouncementXML	Submission_2024-02-23_06:31:46.988.xml
DigitalObjectIdentifier
ReviewLevel	Non peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Leibniz FLI Proteomics
SpeciesList	scientific name: Homo sapiens; common name: human; NCBI TaxID: 9606;
ModificationList	Oxidation; Carbamidomethyl
Instrument	Orbitrap Exploris 480

Revision	Datetime	Status	ChangeLog Entry
0	2023-08-23 05:14:19	ID requested
⏵ 1	2024-02-23 06:31:47	announced

no publication

submitter keyword: Batten disease, glycerophosphodiesters, GPD, CLN3, lysosome

Alessandro Ori
contact affiliation	Leibniz Institute on Aging Fritz Lipmann Institute (FLI)
contact email	alessandro.ori@leibniz-fli.de
lab head
Leibniz FLI Proteomics
contact affiliation	Leibniz FLI
contact email	proteomics@leibniz-fli.de
dataset submitter

MassIVE dataset URI

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