DNA induces folding in α-synuclein:: Understanding the mechanism using chaperone property of osmolytes

a-Synuclein conformational modulation leading to fibrillation has been alpha centrally implicated in Parkinson's disease. Previously, we have shown that alpha-synuclein has DNA binding property. In the present study, we have characterized the effect of DNA binding on the conformation and fibrillation kinetics of a-synuclein. It was observed that single-stranded circular DNA induce a-helix conformation in a-synuclein while plasmid supercoiled DNA has dual effect inducing a partially folded conformation and a-helix under different experimental conditions. Interestingly, a-synuclein showed a specificity for GC* nucleotide sequence in its binding ability to DNA. The aggregation kinetics data showed that DNA which induced partially folded conformation in alpha-symiclein promoted the fibrillation while DNA which induced a-helix delayed the fibrillation, indicating that the partially folded intermediate conformation is critical in the aggregation process. Further, the mechanism of DNA-induced folding/aggregation of alpha-synuclein was studied using effect of osmolytes on alpha-symiclein as a model system. Among the five osmolytes used, Glycerol, trimethylamine-N-oxide, Betaine, and Taurine induced partially folded conformation and in turn enhanced the aggregation of a-symiclein. The ability of DNA and osmolytes in inducing conformational transition in alpha-synuclein, indicates that two factors are critical in modulating a-synuclein folding: (i) electrostatic interaction as in the case of DNA, and (ii) hydrophobic interactions as in the case of osmolytes. The property of DNA inducing a-helical conformation in alpha-synuclein and inhibiting the fibrillation may be of significance in engineering DNA-chip based therapeutic approaches to PD and other amyloid disorders. (c) 2007 Elsevier Inc. All rights reserved.