Effect of amphotericin B on wild-type and mutated prion proteins in cultured cells: Putative mechanism of action in transmissible spongiform encephalopathies

Transmissible spongiform encephalopathies form a group of fatal neurodegene rative disorders that have the unique property of being infectious, sporadi c, or genetic in origin. Although some doubts remain on the nature of the r esponsible agent of these diseases, it is clear that a protein called PrPSc [the scrapie isoform of prion protein (PrP)] plays a central role. PrPSc r epresents a conformational variant of PrPC (the cellular isoform of PrP), t he normal host protein. Polyene antibiotics, such as amphotericin B, have b een shown to delay the accumulation of PrPSc and to increase the incubation time of the disease after experimental transmission in laboratory animals. Unlike agents such as Congo red, the inhibitory effect of amphotericin B o n PrPSc generation has not been observed in infected cultures. Using transf ected cells expressing wild-type or mutated mouse PrPs, we show here that a mphotericin B is able to interfere with the generation of abnormal PrP isof orms in culture. Its action seems related to a modification of PrP traffick ing through the association of this glycosylphosphatidylinositol-anchored p rotein with detergent-resistant microdomains. These results represent a fir st step toward the comprehension of the mechanism of action of amphotericin B in transmissible spongiform encephalopathies.