biostudies-literatureFeringa FMEuropean Union ERC advanced grantLundbeck Foundation347-358https://www.ebi.ac.uk/biostudies/studies/S-EPMC9864589biostudies-literatureUnknown43(3)The presynaptic proteins MUNC18-1, syntaxin-1, and SNAP25 drive SNARE-mediated synaptic vesicle fusion and are also required for neuronal viability. Their absence triggers rapid, cell-autonomous, neuron-specific degeneration, unrelated to synaptic vesicle deficits. The underlying cell death pathways remain poorly understood. Here, we show that hippocampi of <i>munc18-1</i> null mice (unknown sex) express apoptosis hallmarks cleaved caspase 3 (CC-3) and phosphorylated p53, and have condensed nuclei. However, side-by-side <i>in vitro</i> comparison with classical apoptosis induced by camptothecin uncovered striking differences to syntaxin-1 and MUNC18-1 depleted neurons. First, live-cell imaging revealed consecutive neurite retraction hours before cell death in MUNC18-1 or syntaxin-1 depleteThe Journal of neuroscience : the official journal of the Society for NeuroscienceAn Atypical, Staged Cell Death Pathway Induced by Depletion of SNARE-Proteins MUNC18-1 or Syntaxin-1.PMC9864589R277-2018-802322966van Berkel AAFeringa FMVerhage MNair AfalseAn Atypical, Staged Cell Death Pathway Induced by Depletion of SNARE-Proteins MUNC18-1 or Syntaxin-1.The presynaptic proteins MUNC18-1, syntaxin-1, and SNAP25 drive SNARE-mediated synaptic vesicle fusion and are also required for neuronal viability. Their absence triggers rapid, cell-autonomous, neuron-specific degeneration, unrelated to synaptic vesicle deficits. The underlying cell death pathways remain poorly understood. Here, we show that hippocampi of <i>munc18-1</i> null mice (unknown sex) express apoptosis hallmarks cleaved caspase 3 (CC-3) and phosphorylated p53, and have condensed nuclei. However, side-by-side <i>in vitro</i> comparison with classical apoptosis induced by camptothecin uncovered striking differences to syntaxin-1 and MUNC18-1 depleted neurons. First, live-cell imaging revealed consecutive neurite retraction hours before cell death in MUNC18-1 or syntaxin-1 deplete2023-01-01T00:00:00Z2023 Jan2025-04-22T01:07:55.845Z2025-04-05T19:49:49.959ZS-EPMC98645893651723910.1523/JNEUROSCI.0611-22.2022