In silico analysis of the altered protein structure and functions caused by existing synaptic gene mutations in Indian population having neurological disorders
Neurological disorders encompass a diverse range of conditions that affect individuals cognitive, emotional, and social functioning. Though these disorders are multifactorial, genetic factors play a significant role in the pathogenesis. Especially, synaptic gene mutations or synaptic protein dysfunction are shown to be closely associated with neuropathology. This study aims at understanding the critical role of synaptic compartment by conducting comprehensive analysis of existing synaptic gene mutations responsible for the development of three significant disorders in the Indian population: autism spectrum disorder (ASD), epilepsy and schizophrenia (SZ). Our in-silico analysis predicts that mutations in synaptic genes RPL10 (rs387906727), GABRA1 (rs121434579) and DRD2 (rs1801028) corresponding to ASD, epilepsy and SZ respectively, are deleterious. Of these, SZ-related mutations in DRD2 (D(2) dopamine receptor) are deleterious and due to its genetic association also with ASD as well sociosexual behavior, this study focuses on DRD2. In silico analysis using molecular docking revealed an abnormal interaction between D(2) dopamine receptor and neuronal calcium sensor 1, which may hamper neurotransmitter regulation. We further employed a post-weaning social isolation mice model of SZ to investigate the D(2) dopamine receptor expression levels in hippocampus and social behavioral changes. We observed a reduced immunofluorescent intensities of D(2) dopamine receptor and NCS1 compared to group-housed controls in hippocampus and a trend towards an impaired sociosexual behavior characterized by anogenital sniffing in a male-female social interaction test. Altogether, our study helps to further our understanding of synaptic signaling in the context of SZ and decode the probable mechanism by which disrupted synaptic signaling and protein-protein interaction may lead to the disease pathology and further aid in identifying novel therapeutic targets.