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

a-Synuclein conformational modulation leading to fibrillation has been centrally implicated in Parkinson’s disease. Previously, we have
shown that a-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 a-synuclein 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 a-synuclein was studied using effect of osmolytes on a-synuclein 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-synuclein. The ability of DNA and osmolytes in inducing conformational transition in
a-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 a-synuclein and inhibiting
the fibrillation may be of significance in engineering DNA-chip based therapeutic approaches to PD and other amyloid disorders.