Title |
Polythiophenes Inhibit Prion Propagation by Stabilizing Prion Protein (PrP) Aggregates*
|
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Published in |
Journal of Biological Chemistry, April 2012
|
DOI | 10.1074/jbc.m112.355958 |
Pubmed ID | |
Authors |
Ilan Margalith, Carlo Suter, Boris Ballmer, Petra Schwarz, Cinzia Tiberi, Tiziana Sonati, Jeppe Falsig, Sofie Nyström, Per Hammarström, Andreas Åslund, K. Peter R. Nilsson, Alice Yam, Eric Whitters, Simone Hornemann, Adriano Aguzzi |
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. |
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Researcher | 15 | 21% |
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Professor | 5 | 7% |
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