DNA nanostructures prevent the formation of and convert toxic amyloid proteospecies into cytocompatible and biodegradable spherical complexes

Abstract

The deposition of insoluble proteinaceous aggregates in the form of amyloid fibrils within the extracellular space of tissues is associated with numerous diseases. The development of molecular approaches to arrest amyloid formation and prevent cellular degeneration remains very challenging due to the complexity of the process of protein aggregation, which encompasses an infinite array of conformations and quaternary structures. Polyanionic biopolymers, such as glycosaminoglycans and RNAs, have been shown to modulate the self-assembly of amyloidogenic polypeptides and to reduce the toxicity induced by the formation of oligomeric and/or pre-fibrillar proteospecies. This study evaluates the effects of double-stranded DNA (dsDNA) nanostructures (1D, 2D, and 3D) on amyloid self-assembly, fibril disaggregation, and the cytotoxicity associated with amyloidogenesis. Using the islet amyloid polypeptide (IAPP) whose pancreatic accumulation is the hallmark of type 2 diabetes, it was observed that dsDNA nanostructures inhibit amyloid formation by inducing the formation of spherical complexes in which the peptide adopts a random coil conformation. Interestingly, the DNA nanostructures showed a persistent ability to disassemble enzymatically and thermodynamically stable amyloid fibrils into nanoscale DNA/IAPP entities that are fully compatible with β-pancreatic cells and are biodegradable by proteolysis. Notably, dsDNA nanostructures avidly trapped highly toxic soluble oligomeric species in complete cell culture media and converted them into non-toxic binary complexes. Overall, these results expose the potent modulatory effects of dsDNA on amyloidogenic pathways, and these DNA nanoscaffolds could be used as a source of inspiration for the design of molecules to fight amyloid-related disorders.