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α-Synuclein misfolding versus aggregation relevance to Parkinson’s disease: critical

assessment and modeling

Ruben Berrocal, Velmarini Vasquez,  Sambasiva Rao KR, Bharathi S Gadad, Rao KS .

Abstract

α-Synuclein, an abundant and conserved presynaptic brain protein, is implicated as a critical factor in Parkinson’s disease (PD).

The aggregation of the α-synuclein is believed to be a critical event in the disease process. α-synuclein is characterized by a remarkable conformational plasticity, adopting different conformations depending on the environment. Therefore, it is classified as an ‘intrinsically disordered protein’. Recently, a debate has challenged the view on α-synuclein intrinsically disordered behavior 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 doesn’t fit into the normal secondary structural characteristics of proteins?, ii) Potential amino acids involved in complexicity of misfolding in α-synuclein   that leads to aggregation, and iii) Role of metals in misfolding and aggregation. To evaluate the above critical issues, we developed bioinformatics 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 disease.

Ruben Berrocal, Velmarini Vasquez,  Sambasiva Rao KR, Bharathi S Gadad, Rao KS. Molecular Neurobiology, 2014 in press.