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Lookup NU author(s): Professor Matthias TrostORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2023, Springer Nature Limited.Dynamin-1 is a large GTPase with an obligatory role in synaptic vesicle endocytosis at mammalian nerve terminals. Heterozygous missense mutations in the dynamin-1 gene (DNM1) cause a novel form of epileptic encephalopathy, with pathogenic mutations clustering within regions required for its essential GTPase activity. We reveal the most prevalent pathogenic DNM1 mutation, R237W, disrupts dynamin-1 enzyme activity and endocytosis when overexpressed in central neurons. To determine how this mutation impacted cell, circuit and behavioural function, we generated a mouse carrying the R237W mutation. Neurons from heterozygous mice display dysfunctional endocytosis, in addition to altered excitatory neurotransmission and seizure-like phenotypes. Importantly, these phenotypes are corrected at the cell, circuit and in vivo level by the drug, BMS-204352, which accelerates endocytosis. Here, we demonstrate a credible link between dysfunctional endocytosis and epileptic encephalopathy, and importantly reveal that synaptic vesicle recycling may be a viable therapeutic target for monogenic intractable epilepsies.
Author(s): Bonnycastle K, Dobson KL, Blumrich E-M, Gajbhiye A, Davenport EC, Pronot M, Steinruecke M, Trost M, Gonzalez-Sulser A, Cousin MA
Publication type: Article
Publication status: Published
Journal: Nature Communications
Year: 2023
Volume: 14
Issue: 1
Online publication date: 30/08/2023
Acceptance date: 17/08/2023
Date deposited: 27/09/2023
ISSN (electronic): 2041-1723
Publisher: Nature Research
URL: https://doi.org/10.1038/s41467-023-41035-w
DOI: 10.1038/s41467-023-41035-w
Data Access Statement: All relevant data are included in the article and/or its supplementary information files. Source data are provided within this paper. The one exception is the raw proteomic data, which is deposited on PRIDE (Project accession: PXD039667; Project title: Reversal of cell, circuit and seizure phenotypes in a mouse model of DNM1 epileptic encephalopathy; Project webpage: http://www.ebi.ac.uk/pride/archive/projects/PXD039667). Source data are provided with this paper.
PubMed id: 37648685
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