Influence of Surface Functionality of Poly(propylene imine) Dendrimers on Protease Resistance and Propagation of the Scrapie Prion Protein

Publikation: Beitrag in FachzeitschriftForschungsartikelBeigetragenBegutachtung

Beitragende

  • Marlies Fischer - , University College Dublin (Autor:in)
  • Dietmar Appelhans - , Leibniz Institute of Polymer Research Dresden (Autor:in)
  • Simona Schwarz - , Leibniz Institute of Polymer Research Dresden (Autor:in)
  • Barbara Klajnert - , Lodz University of Technology (Autor:in)
  • Maria Bryszewska - , Lodz University of Technology (Autor:in)
  • Brigitte Voit - , Leibniz Institute of Polymer Research Dresden (Autor:in)
  • Mark Rogers - , University College Dublin (Autor:in)

Abstract

Accumulation of PrP(Sc), an insoluble and protease-resistant pathogenic isoform of the cellular prion protein (PrP(C)), is a hallmark in prion diseases. Branched polyamines, including PPI (poly(propylene mime)) dendrimers, are able to remove protease resistant PrP(Sc) and abolish infectivity, offering possible applications for therapy. These dendrimer types are thought to act through their positively charged amino surface groups. In the present study, the molecular basis of the antiprion activity of dendrimers was further investigated, employing modified PPI dendrimers in which the positively charged amino surface groups were substituted with neutral carbohydrate units of maltose (mPPI) or maltotriose (m3PPI). Modification of surface groups greatly reduced the toxicity associated with unmodified PPI but did not abolish its antiprion activity, suggesting that the presence of cationic surface groups is not essential for dendrimer action. PPI and mPPI dendrimers of generation 5 were equally effective in reducing levels of protease-resistant PrP(Sc) (PrP(res)) in a dose- and time-dependent manner in ScN2a cells and in pre-existing aggregates in homogenates from infected brain. Solubility assays revealed that total levels of PrP(Sc) in scrapie-infected mouse neuroblastoma (ScN2a) cells were reduced by mPPI. Coupled with the known ability of polyamino dendrimers to render protease-resistant PrP(Sc) in pre-existing aggregates of PrP(Sc) susceptible to proteolysis, these findings strongly suggest that within infected cells dendrimers reduce total amounts of PrP(Sc) by mediating its denaturation and subsequent elimination.

Details

OriginalspracheEnglisch
Seiten (von - bis)1314-1325
Seitenumfang12
FachzeitschriftBiomacromolecules
Jahrgang11
Ausgabenummer5
PublikationsstatusVeröffentlicht - Mai 2010
Peer-Review-StatusJa
Extern publiziertJa

Externe IDs

PubMed 20405854
Scopus 77952160044
ORCID /0000-0002-4531-691X/work/148607811

Schlagworte

Schlagwörter

  • Gerstmann-straussler syndrome, Poly amidoamine dendrimers, Biological applications, Branched polyamines, Dendritic polymers, Molecular-biology, Infected cells, Variant cjd, Diseases, Transport