Novel SNARE Complex Polymorphisms Associated with Multiple Sclerosis: Signs of Synaptopathy in Multiple Sclerosis

Abstract

Background: It is well known that axonal degeneration plays a role in disability in patients with multiple sclerosis, and synaptopathy has recently become an important issue. Aims: To investigate the possible roles of selected synaptic and presynaptic membrane protein genetic polymorphisms (VAMP2, SNAP-25, synaptotagmin, and syntaxin 1A) in patients with multiple sclerosis. Study Design: Case-control study. Methods: A total of 123 patients with multiple sclerosis and 192 healthy controls were included. The functional polymorphisms of specific SNARE complex proteins (VAMP2, synaptotagmin XI, syntaxin 1A, and SNAP-25) were analyzed by polymerase chain reaction. Results: Significant differences were detected in the genotype and allele distribution of 26-bp Ins/Del polymorphisms of VAMP2 between patients with multiple sclerosis and control subjects; Del/Del genotype and Del allele of VAMP2 were more frequent in patients with multiple sclerosis (p=0.011 and p=0.004, respectively). Similarly, Ddel polymorphism of SNAP-25 gene C/C genotype (p=0.059), syntaxin 1A T/C and C/C genotypes (p=0.005), and synaptotagmin XI gene C allele (p=0.001) were observed more frequently in patients with multiple sclerosis. CC, syntaxin rs1569061 1A gene for 33-bp promoter region TC haplotypes, and synaptotagmin XI gene were found to be associated with an increased risk for multiple sclerosis (p=0.012). Similarly, GC haplotype for rs3746544 of SNAP-25 gene and rs1051312 of SNAP-25 gene were associated with an increased risk for multiple sclerosis (p=0.022). Conclusion: Genetic polymorphisms of SNARE complex proteins, which have critical roles in synaptic structure and communication, may play a role in the development of multiple sclerosis.

VAMP2 Expression and Genotype Are Possible Discriminators in Different Forms of Dementia

“…The VAMP2 gene is located on chromosome 17p13.1 and consists of 6 exons that encode for the SNARE complex key protein required for membrane fusion. A VAMP2 gene 26 bp Ins/Del polymorphism, located in a intergenic region, suspected to be involved in gene expression, distant 2 kb from the 3′ flanking region of VAMP2 was associated with neurological disease like Attention-deficit hyperactivity disorder and with neurodegenerative disease like Multiple Sclerosis ( Sánchez-Mora et al, 2013 ; Kenar et al, 2014 ; Yalın et al, 2019 ). Notably, a reduction of VAMP2 expression in the hippocampus and the entorhinal cortex was found to be associated with cognitive decline ( Sze et al, 2000 ) and AD brains have a reduced level of VAMP2, STX1a and SNAP-25 compared to control brains ( Pham et al, 2010 ).…”

MST1‐knockdown protects against impairment of working memory via regulating neural activity in depression‐like mice

“…Moreover, the level of PSD95 and SYP proteins related to synapse structure was also measured. SYP is a presynaptic vesicle protein that plays an import role in synaptic vesicle release 23 . The lack of SYP may induce a decrease in synaptic vesicles, which can disturb neurotransmitter release and synaptic network activity 24 .…”

“…SYP is a presynaptic vesicle protein that plays an import role in synaptic vesicle release. 23 The lack of SYP may induce a decrease in synaptic vesicles, which can disturb neurotransmitter release and synaptic network activity. 24 It is reported that several synaptic proteins including PSD95 and SYP play an important role in the regulation of the spine formation and synaptic plasticity.…”

Assessment of Stx-1A gene polymorphism (rs1569061) in relation to the development of multiple sclerosis in Egyptian patients

“…7 Recent studies reported that axonal degeneration may be prominent in the beginning of the inflammation period of MS, as well as being one of the major determinants of permanent neurological impairment. 8,9 Synaptopathy, which is defined as the alteration of the synaptic structure and function, has been associated with various neurological diseases, including epilepsy, autism, Alzheimer's disease, and recently MS. Inflammatory-dependent synaptopathy is of particular interest because it is potentially reversible and may represent a novel therapeutic target for MS. 10 At the presynaptic terminal, the membrane fusion process is primarily mediated by the soluble Nethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex. 11 The SNARE complex is mainly composed of three proteins: VAMP-2, syntaxin-1, and SNAP-25.…”