Specific inhibition of pathological prion protein accumulation by small interfering RNAs
Author:
Daude Nathalie1, Marella Mathieu1, Chabry Joëlle1
Affiliation:
1. Institut de Pharmacologie Moléculaire et Cellulaire, UnitéMixte de Recherche 6097, Centre National de la Recherche Scientifique. 660,route des lucioles, 06560 Valbonne, France
Abstract
Development of transmissible spongiform encephalopathies (TSEs)pathogenesis requires the presence of both the normal host prion protein(PrP-sen) and the abnormal pathological proteinase-K resistant isoform(PrP-res). PrP-res forms highly insoluble aggregates, with self-perpetuating properties, by binding and converting PrP-sen molecules into a likeness of themselves. In the present report, we show that small interfering RNA (siRNA)duplexes trigger specific Prnp gene silencing in scrapie-infected neuroblastoma cells. A non-passaged, scrapie-infected culture transfected with siRNA duplexes is depleted of PrP-sen and rapidly loses its PrP-res content. The use of different murine-adapted scrapie strains and host cells did not influence the siRNA-induced gene silencing efficiency. More than 80% of transfected cells were positive for the presence of fluorescein-labeled siRNA duplexes. No cytotoxicity associated with the use of siRNA was observed during the time course of these experiments. Despite a transient abrogation of PrP-res accumulation, our results suggest that the use of siRNA may provide a new and promising therapeutic approach against prion diseases.
Publisher
The Company of Biologists
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