Reduced SNAP25 Protein Fragmentation Contributes to SNARE Complex Dysregulation in Schizophrenia Postmortem Brain.

ABSTRACT: Recent 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?

SUBMITTER: Ramos-Miguel A 

PROVIDER: S-EPMC6588506 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature