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Abstract
Intracerebral 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 40 d followed by an increased rate of PrPsc accumulation at 75 d up to sacrifice. In all PrPsc inoculated animals, clinical symptoms were observed ∼10 d 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.
Highlights
Transmissible spongiform encephalopathies are incurable, fatal neurodegenerative diseases characterized by the accumulation of abnormal prion protein (PrPsc), neuronal cell death and vacuolation of brain [1]
The mean survival time of animals inoculated with 1% PrPsc (1022 dose) combined with 0.9% RADA was 114 d (n = 24) as compared to 78 d (n = 24) for animals that received equivalent PrPsc alone or 80 d (n = 6) for animals inoculated with PrPsc-agarose plugs (Fig. 1A; P,0.001)
This toxicity did not occur in animals that received equivalent doses of PrPsc alone, PrPsc combined with agarose, RADA alone, or normal brain homogenate combined with RADA
Summary
Transmissible spongiform encephalopathies are incurable, fatal neurodegenerative diseases characterized by the accumulation of abnormal prion protein (PrPsc), neuronal cell death and vacuolation of brain [1]. The PrPsc protein is extractable from diseased tissue and is distinguished from endogenous PrPc by partial protease resistance and detergent insolubility [2]. The transmissible agent is the PrPsc protein and it serves as a template for the molecular conversion of endogenous PrPc into the abnormal PrPsc structural isoform [1]. The molecular events that mediate neuronal PrPc to PrPsc conversion, not accumulated PrPsc, appears to be the initiating factor mitigating the neurodegenerative disease process [5]. The mechanism responsible for the conformational conversion of PrPc to an infectious prion remains enigmatic
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