Reduced SNAP25 protein fragmentation contributes to SNARE complex dysregulation in schizophrenia postmortem brain

Publication date: Available online 21 December 2018Source: NeuroscienceAuthor(s): Alfredo Ramos-Miguel, Kristina Gicas, Jehan Alamri, Clare L. Beasley, Andrew J. Dwork, J. John Mann, Gorazd Rosoklija, Fang Cai, Weihong Song, Alasdair M. Barr, William G. HonerAbstractRecent studies associated schizophrenia with enhanced functionality of the presynaptic SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) complex. Altered degradation pathways of the three core SNARE proteins: synaptosomal-associated protein 25 (SNAP25), syntaxin-1 and vesicle-associated membrane protein (VAMP) could contribute to enhanced complex function. To investigate these pathways, we first identified a 15-kDa SNAP25 fragment (f-S25) in human and rat brains, highly enriched in synaptosomal extractions, and mainly attached to cytosolic membranes with low hydrophobicity. The presence of f-S25 is consistent with reports of calpain-mediated SNAP25 cleavage. Co-immunoprecipitation assays showed that f-S25 retains the ability to bind syntaxin-1, which might prevent VAMP and/or Munc18-1 assembly into the complex. Quantitative analyses in postmortem human orbitofrontal cortex (OFC) revealed that schizophrenia (n = 35), but not major depression (n = 15), is associated with lower amounts of f-S25 (–37%, P = 0.027), and greater SNARE protein-protein interactions (35%, P < 0.001), compared with healthy matched controls (n = 28). Enhanced SNARE complex formation was strongly correlated wi...

Source: Neuroscience - December 21, 2018 Category: Neuroscience Source Type: research