Research on Parkinson's disease most often focuses on the ability of the protein α-synuclein (α-syn) to form oligomers and amyloid fibrils, and how such species promote brain death. However, there are indications that α-syn also plays a gene-regulatory role in the cell nucleus. Noncanonical tetrahelical nucleic acids, G-quadruplexes (G4Q), and i-motifs have been shown to play an important role in the control of genomic events. Using the conformation-sensitive single-molecule Förster resonance energy transfer technique we show that monomeric and oligomeric α-syn affect G4Qs and i-motifs in a different way and lead to remodeling of their conformational substates. Aggregated α-syn destabilizes the G4Q leading to unfolding. In contrast, both monomeric and aggregated α-syn enhance folding of the i-motif sequence of telomeric DNA. Importantly, macromolecular crowding is able to partially rescue G4Q from unfolding.
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