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

Irum Javaid Siddiqui,Nashaiman Pervaiz,Amir Ali Abbasi

doi:10.1038/srep24475

Abstract

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.

Highlights

SNCA is a 14.5 kDa, 140 a.a protein encoded by 5 exons with total transcript length of 3041 bps maps on 4q21.3-q22
The first duplication event has transpired at the root of vertebrates, prior to tetrapod-teleost split, deduced in SNCG paralog and ancestor of SNCA/SNCB
It is worth noting that the branch lengths for SNCG proteins are longer than those of other two paralogs, suggesting that this paralog may have rapidly evolved in comparison with SNCA and SNCB

Summary

Introduction

SNCA is a 14.5 kDa, 140 a.a protein encoded by 5 exons with total transcript length of 3041 bps maps on 4q21.3-q22. Oligomeric structure of SNCA is considered as a toxic form but recent observation abolished this hypothesis[10,11]. During the past two decades several hypotheses exist about toxic structural form of SNCA, but none of them are completely consensual. Analysis revealed the sarcopterygian specific origin of SNCA which suggested its lineage specific functional role. On account of this interest, a comparative sequence and structural analysis was performed to estimate the selection and functional constraints on SNCA. In addition variations in domain topologies were explored by comparative analysis of known functional domains of SNCA protein. In light of the findings, it was hypothesized that the region from 32 to 58 of N-terminal lipid binding domain is the most “critical region” of SNCA from evolutionary, functional and disease pathogenesis perspective

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