The Parkinson Disease gene SNCA: Evolutionary and structural insights with pathological implication

After Alzheimer, Parkinson's disease (PD) is the second most common neurodegenerative disorder. Alpha synuclein (SNCA) is deemed as a major component of Lewy bodies, a neuropathological feature of PD. Five point mutations in SNCA have been reported so far, responsible for autosomal dominant PD. This study aims to decipher evolutionary and structural insights of SNCA by revealing its sequence and structural evolutionary patterns among sarcopterygians and its paralogous counterparts (SNCB and SNCG). Rate analysis detected strong purifying selection on entire synuclein family. Structural dynamics divulges that during the course of sarcopterygian evolutionary history, the region encompassed 32 to 58 of N-terminal domain of SNCA has acquired its critical functional significance through the epistatic influence of the lineage specific substitutions. In sum, these findings provide an evidence that the region from 32 to 58 of N-terminal lipid binding alpha helix domain of SNCA is the most critical region, not only from the evolutionary perspective but also for the stability and the proper conformation of the protein as well as crucial for the disease pathogenesis, harboring critical interaction sites.