Permanent URL to this publication: http://dx.doi.org/10.5167/uzh-61798
Margalith, Ilan; Suter, Carlo; Ballmer, Boris; Schwarz, Petra; Tiberi, Cinzia; Sonati, Tiziana; Falsig, Jeppe; Nystrom, Sofie; Hammarstrom, Per; Aslund, Andreas; Nilsson, K Peter R; Yam, Alice; Whitters, Eric; Hornemann, Simone; Aguzzi, Adriano (2012). Polythiophenes inhibit prion propagation by stabilizing PrP aggregates. Journal of Biological Chemistry, 287(23):18872-18887.
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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 COCS, and decreased the amount of PrP(Sc) oligomers that could be captured in an avidity assay. Paradoxically, treatment enhanced the resistance of PrP(Sc) to proteolysis, and triggered the compaction and enhanced the resistance to proteolysis of recombinant mPrP(23-231) fibers. These results suggest that LCPs act as antiprion agents by transitioning PrP aggregates into structures with reduced frangibility. Moreover, ELISA on COCS and in vitro conversion assays with mPrP(23-231) indicated that PTAA 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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|Item Type:||Journal Article, refereed, original work|
|Communities & Collections:||04 Faculty of Medicine > University Hospital Zurich > Institute of Neuropathology|
|DDC:||570 Life sciences; biology
610 Medicine & health
|Deposited On:||20 Apr 2012 07:18|
|Last Modified:||30 Nov 2013 16:59|
|Publisher:||American Society for Biochemistry and Molecular Biology|
|Additional Information:||This research was originally published in Journal of Biological Chemistry. Margalith, Ilan; Suter, Carlo; Ballmer, Boris; Schwarz, Petra; Tiberi, Cinzia; Sonati, Tiziana; Falsig, Jeppe; Nystrom, Sofie; Hammarstrom, Per; Aslund, Andreas; Nilsson, K Peter R; Yam, Alice; Whitters, Eric; Hornemann, Simone; Aguzzi, Adriano (2012). Polythiophenes inhibit prion propagation by stabilizing PrP aggregates. Journal of Biological Chemistry:Epub ahead of print. © the American Society for Biochemistry and Molecular Biology.|
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