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Polythiophenes Inhibit Prion Propagation by Stabilizing Prion Protein (PrP) Aggregates
University of Zurich Hospital, Switzerland .
University of Zurich Hospital, Switzerland .
University of Zurich Hospital, Switzerland .
University of Zurich Hospital, Switzerland .
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2012 (Engelska)Ingår i: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 287, nr 23, s. 18872-18887Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

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 PrPC (PrPSc) oligomers that could be captured in an avidity assay. Paradoxically, 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. 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 PrPSc by stabilizing the conformation of PrPC 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 PrPSc deposits.

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American Society for Biochemistry and Molecular Biology , 2012. Vol. 287, nr 23, s. 18872-18887
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URN: urn:nbn:se:liu:diva-79639DOI: 10.1074/jbc.M112.355958ISI: 000306411900001OAI: oai:DiVA.org:liu-79639DiVA, id: diva2:543971
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Funding Agencies|European Union P-7 Health||Swiss National Foundation||Novartis Research Foundation||European Research Council||Swedish Foundation for Strategic Research|FFL-4|

Tillgänglig från: 2012-08-13 Skapad: 2012-08-13 Senast uppdaterad: 2019-11-08

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Nyström, SofieHammarström, PerÅslund, AndreasNilsson, Peter

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