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PXD039667

PXD039667 is an original dataset announced via ProteomeXchange.

Dataset Summary
TitleReversal of cell, circuit and seizure phenotypes in a mouse model of DNM1 epileptic encephalopathy
DescriptionPathogenic heterozygous missense mutations in the DNM1 gene result in a novel form of epileptic encephalopathy. DNM1 encodes for the large GTPase dynamin-1, an enzyme with an obligatory role in the endocytosis of synaptic vesicles (SVs) at mammalian nerve terminals. Pathogenic DNM1 mutations cluster within regions required for its essential GTPase activity, implicating disruption of this enzyme activity as being central to epileptic encephalopathy. We reveal that the most prevalent pathogenic mutation in the GTPase domain of DNM1, R237W, disrupts dynamin-1 enzyme activity and SV endocytosis when overexpressed in central neurons. To determine how this dominant-negative heterozygous mutant impacted cell, circuit and behaviour when expressed from its endogenous locus, we generated a mouse carrying the R237W mutation. Neurons isolated from heterozygous mice displayed dysfunctional SV endocytosis, which translated into altered excitatory neurotransmission and seizure-like phenotypes. Importantly, these phenotypes were corrected at the cell, circuit and in vivo level by the drug, BMS-204352, which accelerates SV endocytosis in wild-type neurons. This study therefore provides the first direct link between dysfunctional SV endocytosis and epilepsy, and importantly reveals that SV endocytosis is a viable therapeutic route for monogenic intractable epilepsies.
HostingRepositoryPRIDE
AnnounceDate2024-10-22
AnnouncementXMLSubmission_2024-10-22_06:00:15.452.xml
DigitalObjectIdentifier
ReviewLevelPeer-reviewed dataset
DatasetOriginOriginal dataset
RepositorySupportUnsupported dataset by repository
PrimarySubmitterMatthias Trost
SpeciesList scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationListNo PTMs are included in the dataset
InstrumentQ Exactive HF
Dataset History
RevisionDatetimeStatusChangeLog Entry
02023-01-25 09:07:53ID requested
12023-08-14 04:31:06announced
22024-10-22 06:00:15announced2024-10-22: Updated project metadata.
Publication List
Dataset with its publication pending
Keyword List
submitter keyword: synaptic vesicles, epileptic encephalopathy,DNM1
Contact List
Matthias Trost
contact affiliationBiosciences Institute, Newcastle University, Newcastle, UK
contact emailmatthias.trost@ncl.ac.uk
lab head
Matthias Trost
contact affiliationNewcastle University
contact emailmatthias.trost@ncl.ac.uk
dataset submitter
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Dataset FTP location
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PRIDE project URI
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