Prion strain- and species-dependent effects of antiprion molecules in primary neuronal cultures.
Transmissible spongiform encephalopathies (TSE) arise as a consequence of infection of the central nervous system by prions and are incurable. To date, most antiprion compounds identified by in vitro screening failed to exhibit therapeutic activity in animals, thus calling for new assays that could more accurately predict their in vivo potency. Primary nerve cell cultures are routinely used to assess neurotoxicity of chemical compounds. Here, we report that prion strains from different species can propagate in primary neuronal cultures derived from transgenic mouse lines overexpressing ovine, murine, hamster, or human prion protein. Using this newly developed cell system, the activity of three generic compounds known to cure prion-infected cell lines was evaluated. We show that the antiprion activity observed in neuronal cultures is species or strain dependent and recapitulates to some extent the activity reported in vivo in rodent models. Therefore, infected primary neuronal cultures may be a relevant system in which to investigate the efficacy and mode of action of antiprion drugs, including toward human transmissible spongiform encephalopathy agents.
Cronier
Sabrina
S
Unité de Virologie Immunologie Moléculaires, INRA, 78350 Jouy-en-Josas, France.
Beringue
Vincent
V
Bellon
Anne
A
Peyrin
Jean-Michel
JM
Laude
Hubert
H
D000666:Amphotericin B / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D002746:Chlorpromazine / Q000494:pharmacology*; D003224:Congo Red / Q000494:pharmacology*; D006224:Cricetinae; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018621:PrPC Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D018620:PrPSc Proteins / Q000187:drug effects / Q000378:metabolism; D017096:Prion Diseases / Q000378:metabolism; D000072002:Prion Proteins; D011328:Prions / Q000145:classification* / Q000187:drug effects* / Q000378:metabolism; D012608:Scrapie / Q000378:metabolism; D012756:Sheep; D013045:Species Specificity
D018621:PrPC Proteins; D018620:PrPSc Proteins; D000072002:Prion Proteins; D011328:Prions; C512657:Prnp protein, mouse; C074660:MS 8209; D003224:Congo Red; D000666:Amphotericin B; D002746:Chlorpromazine