Abstract
PrPSc, an abnormal conformational isoform of the normal prion protein, PrPC, is the only known component of the prion, a proteinacious agent that causes fatal neurodegenerative disorders in humans and other animals. The hallmark properties of PrPSc are its insolubility in nondenaturing detergents and its resistance to digestion by proteases. Anions such as Congo red (CR) have been shown to reduce the accumulation of PrPSc in a neuroblastoma cell line permanently infected with prions as well as to delay disease onset in rodents when administrated prophylactically. The mechanism by which such anti-prion agents operate is unknown. We show here that in vitro incubation with CR renders native PrPSc resistant to denaturation by boiling SDS. This resulted from PrPSc conformation, since neither the properties of PrPC nor those of predenatured PrPSc were changed by the addition of CR. CR-PrPSc could only be denatured by the addition of acidic 3 M guanidine thiocyanate. Since in vitro conversion experiments have suggested that partial denaturation may be required for PrPSc to serve as template in the PrPC --> PrPSc conversion, we propose that CR inhibits prion propagation by overstabilizing the conformation of PrPSc molecules.
Highlights
PrPSc, an abnormal conformational isoform of the normal prion protein, PrPC, is the only known component of the prion, a proteinacious agent that causes fatal neurodegenerative disorders in humans and other animals
Since in vitro conversion experiments have suggested that partial denaturation may be required for PrPSc to serve as template in the PrPC 3 PrPSc conversion, we propose that Congo red (CR) inhibits prion propagation by overstabilizing the conformation of PrPSc molecules
CR Renders PrPSc Resistant to Denaturation by Boiling SDS—To investigate whether direct interaction of PrPSc with CR may result in inhibition of prion propagation, we tested the biochemical properties of the PrP proteins after incubation of membranes from normal or scrapie-infected hamster brains with CR
Summary
Vol 273, No 6, Issue of February 6, pp. 3484 –3489, 1998 Printed in U.S.A. (Received for publication, August 4, 1997, and in revised form, November 20, 1997). Since in vitro conversion experiments have suggested that partial denaturation may be required for PrPSc to serve as template in the PrPC 3 PrPSc conversion, we propose that CR inhibits prion propagation by overstabilizing the conformation of PrPSc molecules. Prion diseases, such as Creutzfeldt-Jakob disease in humans or scrapie and bovine spongiform encephalopathies in animals, are fatal transmissible neurodegenerative diseases [1]. Diverse sulfated polyanions seem to interfere with the subcellular metabolism of prions in the host cell, for example by altering the recycling of PrP to the interior of the cell [20] None of these reagents were shown to inhibit PrPC production [23]. CR inhibition of prion propagation may result form the inability of CR-PrPSc to convert into the partially denatured molecules required as template in the PrPC 3 PrPSc reaction
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