Dataset Information

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

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

Ramos-Miguel Alfredo A Gicas Kristina K Alamri Jehan J Beasley Clare L CL Dwork Andrew J AJ Mann J John JJ Rosoklija Gorazd G Cai Fang F Song Weihong W Barr Alasdair M AM Honer William G WG

Neuroscience 20181221

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, high ...[more]

PMID: 30579835

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Project description:Schizophrenia (SCZ) is a psychiatric disorder that can include symptoms of disorganized speech and thoughts with uncertain underlying mechanisms possibly linked to over-activated microglia. In this study, we used brain samples from sixteen donors with SCZ and thirteen control donors to assess the differential activation of microglia by quantifying density and 3D reconstruction of microglia stained with ionized calcium-binding adaptor molecule-1 (Iba1). Our samples consisted of sections from the frontal, temporal, and cingulate cortical gray matter, subcortical white matter regions (SCWM), and included the anterior corpus callosum. In the first series of studies, we performed a density analysis followed by a spatial analysis to ascertain the microglial density, distribution, and soma size in SCZ brains. Second, we performed a series of morphological quantification techniques to investigate the arborization patterns of the microglia in SCZ. The results demonstrated an increase in microglia density in the cortical gray matter regions in SCZ cases, while in the SCWM, there was a significant increase in microglia density in the frontal and temporal, but not in the other brain regions of interest (ROIs). Spatial analysis using the "nearest neighbor" demonstrated that there was no effect in "clustering", but there were shorter distances between microglia seen in the SCZ cases. The morphological measures showed that there was a region-dependent increase in the microglia soma size in the SCZ cases while the Sholl analysis revealed a significant decrease in the microglia arborization in the SCZ cases across all the ROI's studied. An in-depth 3D reconstruction of microglia in Brodmann area 9 cortical region found that there was a significant association between age and reduced microglial arborization in the SCZ cases. This region-dependent age association can help determine whether longitudinal changes in microglial activation across age are brain region-dependent, which may point to potential therapeutic targets.

Dataset Information

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

Publications

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

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