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 neurodegenerative disorders that have the unique property of being infectious, sporadic, or genetic in origin. Although some doubts remain on the nature of the responsible agent of these diseases, it is clear that a protein called PrP(Sc) [the scrapie isoform of prion protein (PrP)] plays a central role. PrP(Sc) represents a conformational variant of PrP(C) (the cellular isoform of PrP), the normal host protein. Polyene antibiotics, such as amphotericin B, have been shown to delay the accumulation of PrP(Sc) 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 on PrP(Sc) generation has not been observed in infected cultures. Using transfected cells expressing wild-type or mutated mouse PrPs, we show here that amphotericin B is able to interfere with the generation of abnormal PrP isoforms in culture. Its action seems related to a modification of PrP trafficking through the association of this glycosylphosphatidylinositol-anchored protein with detergent-resistant microdomains. These results represent a first step toward the comprehension of the mechanism of action of amphotericin B in transmissible spongiform encephalopathies.
Mangé
A
A
Institut de Génétique Humaine, CNRS UPR 1142, Montpellier, France.
Milhavet
O
O
McMahon
H E
HE
Casanova
D
D
Lehmann
S
S
D000666:Amphotericin B / Q000494:pharmacology*; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003902:Detergents / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance; D051379:Mice; D008815:Mice, Inbred Strains; D009154:Mutation; D017096:Prion Diseases / Q000635:transmission; D011328:Prions / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism*; D013997:Time Factors; D014018:Tissue Distribution
D003902:Detergents; D011328:Prions; D000666:Amphotericin B