RT Journal Article
SR Electronic
T1 Dysregulation of Synaptic and Developmental Transcriptomic/Proteomic Profiles upon Depletion of MUNC18-1
JF eneuro
JO eNeuro
FD Society for Neuroscience
SP ENEURO.0186-22.2022
DO 10.1523/ENEURO.0186-22.2022
VO 9
IS 6
A1 Annemiek A. Van Berkel
A1 Frank Koopmans
A1 Miguel Angel Gonzalez-Lozano
A1 Hanna C. A. Lammertse
A1 Femke Feringa
A1 Julien Bryois
A1 Patrick F. Sullivan
A1 August B. Smit
A1 Ruud F. Toonen
A1 Matthijs Verhage
YR 2022
UL http://www.eneuro.org/content/9/6/ENEURO.0186-22.2022.abstract
AB Absence of presynaptic protein MUNC18-1 (gene: Stxbp1) leads to neuronal cell death at an immature stage before synapse formation. Here, we performed transcriptomic and proteomic profiling of immature Stxbp1 knock-out (KO) cells to discover which cellular processes depend on MUNC18-1. Hippocampi of Stxbp1 KO mice showed cell type-specific dysregulation of 2123 transcripts primarily related to synaptic transmission and immune response. To further investigate direct, neuron-specific effects of MUNC18-1 depletion, a proteomic screen was performed on murine neuronal cultures at two developmental timepoints before onset of neuron degeneration. 399 proteins were differentially expressed, which were primarily involved in synaptic function (especially synaptic vesicle exocytosis) and neuron development. We further show that many of the downregulated proteins on loss of MUNC18-1 are normally upregulated during this developmental stage. Thus, absence of MUNC18-1 extensively dysregulates the transcriptome and proteome, primarily affecting synaptic and developmental profiles. Lack of synaptic activity is unlikely to underlie these effects, as the changes were observed in immature neurons without functional synapses, and minimal overlap was found to activity-dependent proteins. We hypothesize that presence of MUNC18-1 is essential to advance neuron development, serving as a “checkpoint” for neurons to initiate cell death in its absence.