α-Synuclein misfolding versus aggregation relevance to Parkinson’s disease: Critical assessment and modeling

Abstract

α-Synuclein, an abundant and conserved presynaptic brain protein, is implicated as a critical factor in Parkinson’s disease (PD). The aggregation of α-synuclein isbelieved to be a critical event in the isease process. α-Synuclein is characterized by a remarkable conformational plasticity, adopting different onformations depending on the environment. Therefore, it is classified as an “intrinsically disordered protein.” Recently, a debate has challenged theview on the intrinsically disordered behavior of α-synuclein in the cell. It has been proposed that α-synuclein is a stable tetramer with a low propensity for aggregation; however, its destabilization leads to protein misfolding and its aggregation kinetics. In our critical analysis, we discussed about major issues: (i) why α-synuclein conformational behavior does not fit into the normal secondary structural characteristics of proteins, (ii) potential amino acids involved in the complexity of misfolding in α-synuclein that leads to aggregation, and (iii) the role of metals in misfolding and aggregation. To evaluate the above critical issues, we developed ioinformatics models related to secondary and tertiary conformations, Ramachandran plot, free energy change, intrinsic disordered prediction, solvent accessibility, and FoldIndex pattern. To the best of our knowledge, this is a novel critical assessment to understand the misfolding biology of synuclein and its relevance to Parkinson’s disease.