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

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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.

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Acknowledgments

The authors thank Melo Brain Grant and Melo Bioinformatics facility for support. Rao KS is thankful to the National Science Investigation (SNI) of SENACYT, Republic of Panama for partial financial support. Velmarini Vasquez is supported by a doctoral scholarship granted by the Institute for Training and Development of Human Resources of Panama (IFARHU) and the National Secretariat for Science, Technology, and Innovation of Panama (SENACYT).

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Authors and Affiliations

  1. Centre for Neuroscience, Institute for Scientific Research and Technology Services (INDICASAT-AIP), City of Knowledge, Republic of Panama

    Ruben Berrocal, Velmarini Vasquez, Sambasiva Rao KRS & Rao KS

  2. Department of Biotechnology, Acharya Nagarjuna University, Guntur, India

    Ruben Berrocal, Velmarini Vasquez & Sambasiva Rao KRS

  3. Department of Psychiatry, UT Southwestern Medical Center at Dallas, Dallas, TX, 75390, USA

    Bharathi S Gadad

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  1. Ruben Berrocal
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  2. Velmarini Vasquez
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  3. Sambasiva Rao KRS
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  4. Bharathi S Gadad
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Correspondence to Bharathi S Gadad or Rao KS.

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Ruben Berrocal and Velmarini Vasquez are equally first authors.

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Berrocal, R., Vasquez, V., KRS, S.R. et al. α-Synuclein Misfolding Versus Aggregation Relevance to Parkinson’s Disease: Critical Assessment and Modeling. Mol Neurobiol 51, 1417–1431 (2015). https://doi.org/10.1007/s12035-014-8818-2

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