TY - JOUR
T1 - α-Synuclein Misfolding Versus Aggregation Relevance to Parkinson’s Disease
T2 - Critical Assessment and Modeling
AU - Berrocal, Ruben
AU - Vasquez, Velmarini
AU - KRS, Sambasiva Rao
AU - Gadad, Bharathi S.
AU - KS, Rao
N1 - Publisher Copyright:
© 2014, Springer Science+Business Media New York.
PY - 2015/6/1
Y1 - 2015/6/1
N2 - 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.
AB - 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.
KW - Aggregation
KW - Conformation
KW - Metals
KW - Misfolding
KW - Parkinson’s disease
KW - α-Synuclein
UR - http://www.scopus.com/inward/record.url?scp=84939896736&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84939896736&partnerID=8YFLogxK
U2 - 10.1007/s12035-014-8818-2
DO - 10.1007/s12035-014-8818-2
M3 - Review article
C2 - 25139280
AN - SCOPUS:84939896736
SN - 0893-7648
VL - 51
SP - 1417
EP - 1431
JO - Molecular Neurobiology
JF - Molecular Neurobiology
IS - 3
ER -