In Silico Analysis of Structural and Functional Impacts of Missense SNPs of SNCA Gene in Parkinson’s Disease

Abstract

Aim: Synuclein alpha (SNCA), the first gene identified as genetically associated with Parkinson’s disease (PD), encodes the α-synuclein protein, which plays a role in synaptic function. Parkinson’s disease is a progressive neurodegenerative disorder characterized by the abnormal accumulation and aggregation of α-synuclein and clinically presents with motor dysfunction such as tremor, bradykinesia, rigidity, and postural instability. Structural alterations in SNCA are thought to contribute to disease pathogenesis by promoting the misfolding of the α-synuclein protein, disrupting its stability, and leading to the formation of pathological aggregates. Material and Method: In this study, the structural and functional effects of missense single nucleotide polymorphisms (SNPs) in SNCA were evaluated through comprehensive in silico analyses. First, gene–gene and protein–protein interaction networks were analyzed to identify functional partners of SNCA, and the evolutionary conservation of amino acid positions was assessed. A total of 245 missense SNPs were analyzed using SIFT, PANTHER, PolyPhen-2, and PredictProtein, and 25 SNPs were predicted to be potentially deleterious. Further analysis with machine learningbased tools, including PhD-SNP and SNPs&GO, revealed 14 disease- related SNPs, among which nine were consistently predicted as deleterious across all tools. Protein stability was evaluated using I-Mutant2.0, MUpro, and Meta-SNP, identifying 5 SNPs as potentially pathogenic. Results: These five variants were located within the functionally and evolutionarily conserved N-terminal region of α-synuclein, and structural analyses suggested that they may impair protein stability and promote aggregation. Conclusion: Overall, these findings highlight the pathogenic potential of missense SNPs in SNCA and provide strong candidates for future functional validation studies.

Keywords

• SNCA
• alpha synuclein
• Parkinson’s disease
• single nucleotide polymorphism (SNP)
• in silico

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