Matches in SemOpenAlex for { <https://semopenalex.org/work/W4377242500> ?p ?o ?g. }
- W4377242500 abstract "Abstract SNAP25 is one of three neuronal SNAREs driving synaptic vesicle exocytosis. We studied three mutations in SNAP25 that cause epileptic encephalopathy: V48F, and D166Y in the Synaptotagmin-1 (Syt1) binding interface, and I67N, which destabilizes the SNARE-complex. All three mutations reduced Syt1-dependent vesicle docking to SNARE-carrying liposomes and Ca 2+ -stimulated membrane fusion in vitro and in neurons. The V48F and D166Y mutants (with potency D166Y > V48F) led to reduced Readily Releasable Pool (RRP) size, due to increased spontaneous (mEPSC) release and decreased priming rates. These mutations lowered the energy barrier for fusion and increased the release probability, which are gain-of-function features not found in Syt1 knockout (KO) neurons; normalized mEPSC release rates were higher (potency D166Y>V48F) than in the Syt1 KO. These mutations (potency D166Y > V48F) increased spontaneous association to partner SNAREs, resulting in unregulated membrane fusion. In contrast, the I67N mutant decreased mEPSC frequency and EPSC amplitudes due to an increase in the apparent height of the energy barrier for fusion, whereas the RRP size was unaffected. This could be partly compensated by positive charges lowering the energy barrier. Overall, pathogenic mutations in SNAP25 cause complex changes in the energy landscape for priming and fusion." @default.
- W4377242500 created "2023-05-23" @default.
- W4377242500 creator A5006117015 @default.
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- W4377242500 creator A5064248367 @default.
- W4377242500 creator A5091994492 @default.
- W4377242500 date "2023-05-21" @default.
- W4377242500 modified "2023-09-26" @default.
- W4377242500 title "SNAP25 disease mutations change the energy landscape for synaptic exocytosis due to aberrant SNARE interactions" @default.
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- W4377242500 doi "https://doi.org/10.1101/2023.05.21.541607" @default.