SNAP25

Protein coding gene in the species Homo sapiens

Synaptosomal Associated Protein, 25kDa (SNAP 25) is a Target Soluble NSF (N ethylmaleimide sensitive factor) Attachment Protein Receptor (t SNARE) protein encoded by the SNAP25 gene found on chromosome 20p12.2 in humans. SNAP 25 is a component of the trans SNARE complex, which accounts for membrane fusion specificity and directly executes fusion by forming a tight complex that brings the synaptic vesicle and plasma membranes together.

Individuals harboring pathogenic heterozygous de novo missense or loss of function variants in SNAP 25 often present with an early onset developmental and epileptic encephalopathy. The core symptoms comprise intellectual disability ranging between mild to profound and early onset seizures mostly occurring before the age of two years. Further recurrent symptoms include movement disorders, cerebral visual impairment, and brain atrophy. Electrophysiological studies identified aberrant spontaneous neurotransmission as causative and suggest that structurally clustered pathogenic variants lead to similar synaptic phenotypes.

Consistent with the regulation of synaptic Ca2+ responsiveness, heterozygous deletion of the SNAP 25 gene in mice results in a hyperactive phenotype similar to attention deficit hyperactivity disorder (ADHD). In heterozygous mice, a decrease in hyperactivity is observed with dextroamphetamine (or Dexedrine), an active ingredient in the ADHD drug Adderall. Homozygous deletions of the SNAP 25 gene are lethal. An additional study indicated that incorporation of a SNAP 25 transgene back into the heterozygous SNAP 25 mutant mouse can rescue normal activity levels similar to wildtype mice. This suggests that low protein levels of SNAP 25 can be a cause of hyper kinetic behavior. Subsequent studies have suggested that at least some of the SNAP 25 gene mutations in humans might predispose to ADHD. Identification of polymorphisms in the 3’ untranslated region of the SNAP 25 gene was established in linkage studies with families that had been pre diagnosed ADHD.

Studies in the post mortem brains of patients with Schizophrenia have shown that altered protein levels of SNAP 25 are specific to regions of the brain. Reduced SNAP 25 protein expression has been observed in the hippocampus as well as an area of the frontal lobe known as Broadman's area 10 whereas SNAP 25 expression has increased in both the cingulate cortex and prefrontal lobe of Broadman's area 9. The varying levels of SNAP 25 protein found in different areas of the brain have been thought to contribute to the conflicting psychological behaviors (depressive vs. hyperactive) expressed in some Schizophrenic patients. The blind drunk (Bdr) mouse model which has a point mutations in the SNAP 25b protein has provided a complex phenotype involving behaviors such as an abnormal circadian rhythm, uncoordinated gait, and disinterest in new objects/toys. Another mouse model generated from Cre LoxP recombination, showed that conditional knockout (cKO) of the SNAP 25 gene in the forebrain, showed inactive SNAP 25 gene expression in glutamatergic neurons. However, significant glutamate levels were found in the cortex of these cKO mice. These mice also exhibited deficient social skills, impaired learning and memory, enhanced kinesthetic activity, a reduced startle response, impaired self care, nursing ability and nest building skills. Antipsychotic drugs such as Clozapine and Riluzole have been shown to significantly reduce the schizophrenic phenotype expressed in SNAP 25 cKO mice. In five distinct regions of the brain, low levels of SNAP 25 can be seen in patients with Alzheimer's.

A single nucleotide polymorphism in the SNAP 25 gene promoter has been shown to influence the expression levels of the SNAP 25b isoform in the prefrontal cortex. Increased levels of SNAP 25b have been shown to impair synaptic transmission and maturation which could lead to early onset bipolar disorder (EOBD). The most abundant isoform of SNAP 25 is SNAP 25a during the early weeks of development in mice however in adulthood there is a change and the SNAP 25b isoform increases in the brain. This is shown to correlate with adolescent humans being increasingly diagnosed with EOBD during puberty. It has been suggested that early onset bipolar disorder is more closely linked to Schizophrenia than to Bipolar Disorder itself. The single nucleotide polymorphism of SNAP 25 (rs6039769) associated with EOBD has been shown to increase the risk of patients developing Schizophrenia. Botulinum toxins A, C and E cleave SNAP 25, leading to paralysis in clinically developed botulism.

Deletion of the SNAP 25b isoform has been shown to cause developmental abnormalities and seizures in mice. High levels of SNAP 25a and the protein syntaxin appear to be linked to seizures found in infantile epilepsy. SNAP 25 knock in mice have distinct phenotypic behavior similar to the fits and seizures of epileptic patients, as well as anxiety.

In the coloboma hyperactive mutant mouse model where SNAP 25 protein levels are reduced to 50% of the normal level, depolarized neurotransmitter release of dopamine and serotonin were reduced as well as glutamate release. The reduction in glutamate levels can lead to deficient memory and increased learning disabilities. Certain polymorphisms of SNAP 25 (rs363043, rs353016, rs363039, rs363050) have been shown to affect the cognitive behavior, specifically the Intelligence Quotient (IQ)), of patients without pre existing neurological diseases.

SNAP 25 protein expression can be altered by sex hormone levels in neonatal rats. Male rats that received an antiestrogen drug showed a 30% decrease in SNAP 25 levels and females treated with estrogen or testosterone showed a 30% increase in SNAP 25 levels. This suggests that synaptosomal proteins, such as SNAP 25, may have a dependence on neonatal hormone levels during brain development in rats. An additional study, showed that SNAP 25 levels in the hippocampus of the brain in neonatal mice were altered if the mother had been exposed to human influenza virus during pregnancy.