Submitted to: PLOS ONE
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/28/2008
Publication Date: 2/12/2009
Citation: Hnasko, R.M., Bruederle, C.E. 2009. Inoculation of Scrapie with the Self-Assembling RADA-Peptide Disrupts Prion Accumulation and Extends Hamster Survival. PLoS ONE. 4(2): http://www.plosone.org/article/info:doi/10.1371/journal.pone.0004440
Interpretive Summary: We have identified a synthetic 16-amino acid RADA peptide repeat that binds the prion protein and increases animal survival >30% following inoculation into the brain. The RADA peptide self-assembles into a network of nano-filaments that is effective in promoting tissue regeneration and neuronal recovery following injury. In this report we show that combined prion-RADA inoculation results a significant delay in the onset of disease symptoms, increased time of animal survival, and an altered rate of prion accumulation. There is a time-dependent elevation in glial cell protein markers with associated reactive gliosis consistent with enhanced neuroprotective activity. Moreover, we demonstrate that the anti-prion compound Congo Red competes with the RADA peptide for prion binding, suggesting both compounds share a similar prion binding site and mechanism to disrupt the rate of prion accumulation. We conclude that RADA disrupts the pathogenesis of prion disease by altering the rate of prion accumulation by enhanced neuroprotective activity of glia cells. This is the first demonstration that a small synthetic peptide can disrupt the pathogenesis of prion disease and extend animal survival.
Technical Abstract: Intercerebral inoculation of 263K Scrapie brain homogenate (PrPsc) with a self-assembling RADA-peptide (RADA) significantly delayed disease onset and increased hamster survival. Time of survival was dependent on the dose of RADA and pre-incubation with PrPsc prior to inoculation. RADA treatment resulted in the absence of detectable PrPsc at 40d followed by an increased rate of PrPsc accumulation at 75d up to sacrifice. In all PrPsc inoculated animals, clinical symptioms were observed~10d prior to sacrifice and brains showed spongiform degeneration with Congo red positive plaques. A time-dependent increase in reactive gliosis was observed in both groups with more GFAP detected in RADA treated animals at all time points. The PrP protein showed dose-dependent binding to RADA and this binding was competitively inhibited by Congo Red. We conclude that RADA disrupts the efficacy of prion transmission by altering the rate of PrPsc accumulation. This is the first demonstration that a self-assembling biomolecular peptide can interact with PrPsc, disrupt the course of Scrapie disease process, and extend survival.