Abstract
Luminescent conjugated polymers (LCPs) interact with ordered protein aggregates and sensitively detect amyloids of many different proteins, suggesting that they may possess antiprion properties. Here, we show that a variety of anionic, cationic, and zwitterionic LCPs reduced the infectivity of prion-containing brain homogenates and of prion-infected cerebellar organotypic cultured slices and decreased the amount of scrapie isoform of PrP(C) (PrP(Sc)) oligomers that could be captured in an avidity assay. Paradoxically, treatment enhanced the resistance of PrP(Sc) to proteolysis, triggered the compaction, and enhanced the resistance to proteolysis of recombinant mouse PrP(23-231) fibers. These results suggest that LCPs act as antiprion agents by transitioning PrP aggregates into structures with reduced frangibility. Moreover, ELISA on cerebellar organotypic cultured slices and in vitro conversion assays with mouse PrP(23-231) indicated that poly(thiophene-3-acetic acid) may additionally interfere with the generation of PrP(Sc) by stabilizing the conformation of PrP(C) or of a transition intermediate. Therefore, LCPs represent a novel class of antiprion agents whose mode of action appears to rely on hyperstabilization, rather than destabilization, of PrP(Sc) deposits.
Highlights
Luminescent conjugated polymers (LCPs) are highly specific to amyloid conformations and may represent potential antiprion compounds
We show that a variety of anionic, cationic, and zwitterionic LCPs reduced the infectivity of prioncontaining brain homogenates and of prion-infected cerebellar organotypic cultured slices and decreased the amount of scrapie isoform of PrPC (PrPSc) oligomers that could be captured in an avidity assay
To validate that the increased PK resistance of PrPSc in PTAA-treated RML6 brain homogenates and prion-infected slice cultures can be ascribed to a direct interaction of PTAA on PrPSc independently of the sample environment, we investigated whether PTAA renders mPrP[23–231] fibers more stable to PK digestion. mPrP[23–231] fibers were incubated with 10 g mlϪ1 PTAA prior to limited proteolysis with different PK concentrations and immunoblotting
Summary
Luminescent conjugated polymers (LCPs) are highly specific to amyloid conformations and may represent potential antiprion compounds. Significance: LCPs may represent novel pharmacophores for the prevention and treatment of prion diseases. We show that a variety of anionic, cationic, and zwitterionic LCPs reduced the infectivity of prioncontaining brain homogenates and of prion-infected cerebellar organotypic cultured slices and decreased the amount of scrapie isoform of PrPC (PrPSc) oligomers that could be captured in an avidity assay. Treatment enhanced the resistance of PrPSc to proteolysis, triggered the compaction, and enhanced the resistance to proteolysis of recombinant mouse PrP[23– 231] fibers. These results suggest that LCPs act as antiprion agents by transitioning PrP aggregates into structures with reduced frangibility. Prion diseases are neurodegenerative infectious disorders characterized by the deposition of -sheet-rich aggregates. It is likely that the interaction of such compounds with infec-
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