α-Synuclein Misfolding Versus Aggregation Relevance to Parkinson’s Disease: Critical Assessment and Modeling

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

Research output: Contribution to journalReview article

12 Scopus citations

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 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 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 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’s disease.

Original languageEnglish (US)
Pages (from-to)1417-1431
Number of pages15
JournalMolecular Neurobiology
Volume51
Issue number3
DOIs
Publication statusPublished - Jun 1 2015

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Keywords

  • Aggregation
  • Conformation
  • Metals
  • Misfolding
  • Parkinson’s disease
  • α-Synuclein

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience

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