Abnormalities of SNARE Mechanism Proteins in Anterior Frontal Cortex in Severe Mental Illness

Abstract

A fundamental molecular component of neural connectivity is the SNARE (SNAP receptor) protein complex, which consists of three proteins, syntaxin, SNAP-25 and VAMP. Under appropriate conditions, the SNARE complex can be formed in vitro. To investigate the hypothesis that dysregulation of SNARE proteins or their interactions could be abnormal in severe mental disorders, the three SNARE proteins and the complex were studied in post-mortem anterior frontal cortex homogenates. An ELISA was used to quantify SNARE protein immunoreactivities in cortical homogenates from four groups: patients with schizophrenia who died of causes other than suicide (n = 6), patients with schizophrenia and suicide (n = 7), patients with depression and suicide (n = 11), and controls (n = 11). Differences between groups in patterns of SNARE protein immuno-reactivities were demonstrated [Wilks' Lambda F(9,68) = 3.57, P = 0.001]. Protein-by-protein analyses indicated a significant reduction in SNAP-25 immunoreactivity in the schizophrenia non-suicide group [28% decrease relative to controls, F(3,31) = 6.45, P = 0.002, Student-Newman-Keuls test, P < 0.01]. The intercorrelations between SNARE protein and synaptophysin immunoreactivities were high in controls, but lower in the other groups, further indicating disturbances in relationships between these proteins. The extent of SNARE complex formation in vitro was studied using immuno-blotting. Significant differences related to group membership were observed for the SNARE complexes identified by SNAP-25 [Wilks' Lambda F(3,31) = 4.76, P = 0.008] and by syntaxin immunostaining [Wilks' Lambda F(3,31) = 9.16, P = 0.0002]. In both groups with suicide as a cause of death, relatively more SNAP-25 and syntaxin was present in the heterotrimeric SNARE complex than in other molecular forms. These abnormalities in the SNARE complex could represent a molecular substrate for abnormalities of neural connectivity in severe mental disorders.

Proteomic analysis of membrane microdomain-associated proteins in the dorsolateral prefrontal cortex in schizophrenia and bipolar disorder reveals alterations in LAMP, STXBP1 and BASP1 protein expression

“…75 Further expression studies of proteins involved in neurite formation in these diseases are required to strengthen a hypothesis such as this. It is worth noting that previous expression studies in SCZ and BPD generally reported a tendency towards a reduced expression in SCZ and BPD, 76,77 with increases in some synaptic-associated proteins, such as SNAP-25 60 and conflicting reports regarding other such as GAP-43 and synaptophysin. 37,[78][79][80][81][82] A strength of the current investigation is the use of two complementary proteomic approaches, 2D DIGE and GeLC-MS/MS to identify candidate diseaseassociated proteins within the MM proteome in SCZ and BPD.…”

“…55 Several studies have examined syntaxin expression in SCZ and have demonstrated an increase in the mRNA level in the temporal cortex 56 and in protein levels in the cingulate cortex. 57,58 However, no changes were reported in total syntaxin protein expression in the parietal cortex, 57 temporal cortex, 57 frontal cortex 57,59,60 or the cerebellum 61 in SCZ. Future studies would need to examine (i) the relationship of STXBP1 with syntaxin and SNARE complex formation as well as (ii) the expression of both proteins across several brain regions in SCZ.…”

A SNAP25 promoter variant is associated with early-onset bipolar disorder and a high expression level in brain

“…A previous study reported a significant increase of SNAP25 and syntaxin interaction in subjects who died by suicide. 31 Thus, we carried out an additional analysis taking into account the suicide status of subjects. However, no significant effect of suicide status was observed on this sample (Student's t-test, P SNAP25a = 0.58 and P SNAP25b = 0.36).…”

Abnormalities of myelination in schizophrenia detected in vivo with MRI, and post-mortem with analysis of oligodendrocyte proteins

“…These samples were used in previous studies, and descriptions of individual cases are available. 31,39 We used well-characterized antibodies reactive with MAG (Boehringer Mannheim, Laval, Canada) 40 and with CNPase (SMI-91, Sternberger, Lutherville, MD, USA). 34 Prior to using an ELISA to quantify the oligodendrocyte-associated proteins MAG and CNPase, we performed immunoblotting studies of human brain homogenates, which confirmed the expected single band at approximately 100 kDa for MAG and the doublet band at approximately 45-50 kDa for CNPase.…”