Comparative protein structural analyses of α-synuclein linked pathogenic variants reveal the role of N-terminally located critical region in Parkinson’s disease pathogenesis

SNCA was the first gene to be linked to Parkinson's disease (PD). Pathogenic variations in the corresponding neuronal protein α-synuclein are known to induce its aggregation to cytotoxic oligomers that ultimately manifest as Lewy bodies, the histopathological hallmark lesions of PD. Previously we evaluated the protein structural effects of subset of PD associated pathogenic variants of the α-synuclein. This data revealed that a protein segment 32 aa – 58 aa (aa: amino acids) within N-terminal domain of α-synuclein plays a critical role in PD pathogenesis through epistatic effect of missense variants. The present study evaluates the protein structural effects of six recently reported PD associated missense variants of α-synuclein. Previously, comparative protein structural modeling revealed the significant conformational deviations of five PD-causing missense variants of α-synuclein (A30P, E46K, H50Q, G51D, and A53T) from wild-type protein structure. In line with our previously reported data, a major protein conformational deviation of these recently reported missense variants was noticed within protein segment 32 aa-58 aa of SNCA protein. Protein–protein interaction analysis revealed that residues within this segment of α-synuclein participate in direct interaction with STXBP1, a protein that is involved in early-onset neurocognitive conditions. The present results taken together with our previously reported data demonstrate that the N–terminally located protein segment (32 aa – 58 aa) might be crucial for the proper conformation of the α-synuclein and harbor critical interaction sites. These findings may facilitate clarifying molecular mechanisms underlying the synucleinopathies and identification of novel therapeutic targets.