PXD039667

PXD039667 is an original dataset announced via ProteomeXchange.

Title	Reversal of cell, circuit and seizure phenotypes in a mouse model of DNM1 epileptic encephalopathy
Description	Pathogenic 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.
HostingRepository	PRIDE
AnnounceDate	2024-10-22
AnnouncementXML	Submission_2024-10-22_06:00:15.452.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Matthias Trost
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	No PTMs are included in the dataset
Instrument	Q Exactive HF

Revision	Datetime	Status	ChangeLog Entry
0	2023-01-25 09:07:53	ID requested
1	2023-08-14 04:31:06	announced
⏵ 2	2024-10-22 06:00:15	announced	2024-10-22: Updated project metadata.

Dataset with its publication pending

submitter keyword: synaptic vesicles, epileptic encephalopathy,DNM1

Matthias Trost
contact affiliation	Biosciences Institute, Newcastle University, Newcastle, UK
contact email	matthias.trost@ncl.ac.uk
lab head
Matthias Trost
contact affiliation	Newcastle University
contact email	matthias.trost@ncl.ac.uk
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/2023/08/PXD039667

PRIDE project URI

• PRIDE
  1. PXD039667
     1. Label: PRIDE project
     2. Name: Reversal of cell, circuit and seizure phenotypes in a mouse model of DNM1 epileptic encephalopathy