The deposition of insoluble proteinaceous aggregates in the form of amyloidfibrils within the extracellular space of tissues is associated with numerous diseases.The development of molecular approaches to arrest amylo...The deposition of insoluble proteinaceous aggregates in the form of amyloidfibrils within the extracellular space of tissues is associated with numerous diseases.The development of molecular approaches to arrest amyloid formation and prevent cel-lular 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 polypep-tides 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 dis-aggregation,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 per-sistent ability to disassemble enzymatically and thermodynamically stable amyloidfibrils into nanoscale DNA/IAPP entities that are fully compatible withβ-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 tofight amyloid-related disorders.展开更多
基金Natural Sciences and Engineering Research Council of Canada,Grant/Award Numbers:RGPIN-2018-06209,RGPIN-2021-03301,RGPIN-2018-05799。
文摘The deposition of insoluble proteinaceous aggregates in the form of amyloidfibrils within the extracellular space of tissues is associated with numerous diseases.The development of molecular approaches to arrest amyloid formation and prevent cel-lular 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 polypep-tides 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 dis-aggregation,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 per-sistent ability to disassemble enzymatically and thermodynamically stable amyloidfibrils into nanoscale DNA/IAPP entities that are fully compatible withβ-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 tofight amyloid-related disorders.
