Antiprion activity of cholesterol esterification modulators: a comparative study using ex vivo sheep fibroblasts and lymphocytes and mouse neuroblastoma cell lines.
Our studies on the role of cholesterol homeostasis in the pathogenesis of scrapie revealed abnormal accumulation of cholesterol esters in ex vivo peripheral blood mononuclear cells (PBMCs) and skin fibroblasts from healthy and scrapie-affected sheep carrying a scrapie-susceptible genotype compared to sheep with a resistant genotype. Similar alterations were observed in mouse neuroblastoma N2a cell lines persistently infected with mouse-adapted 22L and RML strains of scrapie that showed up to threefold-higher cholesterol ester levels than parental N2a cells. We now report that proteinase K-resistant prion protein (PrPres)-producing cell populations of subclones from scrapie-infected cell lines were characterized by higher cholesterol ester levels than clone populations not producing PrPres. Treatments with a number of drugs known to interfere with different steps of cholesterol metabolism strongly reduced the accumulation of cholesterol esters in ex vivo PBMCs and skin fibroblasts from scrapie-affected sheep but had significantly less or no effect in their respective scrapie-resistant or uninfected counterparts. In scrapie-infected N2a cells, inhibition of cholesterol esters was associated with selective antiprion activity. Effective antiprion concentrations of cholesterol modulators (50% effective concentration [EC(50)] range, 1.4 to 40 microM) were comparable to those of antiprion reference compounds (EC(50) range, 0.6 to 10 microM). These data confirm our hypothesis that abnormal accumulation of cholesterol esters may represent a biological marker of susceptibility to prion infection/replication and a novel molecular target of potential clinical importance.
Pani
Alessandra
A
Department of Biomedical Sciences and Technologies, University of Cagliari, 09042-Monserrato, Italy. pania@unica.it
Norfo
Claudia
C
Abete
Claudia
C
Mulas
Claudia
C
Putzolu
Marirosa
M
Laconi
Sergio
S
Orrù
Christina Doriana
CD
Cannas
M Dolores
MD
Vascellari
Sarah
S
La Colla
Paolo
P
Dessì
Sandra
S
D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism*; D002788:Cholesterol Esters / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004951:Esterification / Q000187:drug effects; D000068338:Everolimus; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D005838:Genotype; D008214:Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D009447:Neuroblastoma / Q000378:metabolism / Q000473:pathology; D000077205:Pioglitazone; D011328:Prions / Q000187:drug effects*; D012608:Scrapie / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D012756:Sheep; D012757:Sheep Diseases / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D020123:Sirolimus / Q000031:analogs & derivatives / Q000494:pharmacology; D045162:Thiazolidinediones / Q000494:pharmacology
D002788:Cholesterol Esters; D011328:Prions; D045162:Thiazolidinediones; D002784:Cholesterol; D000068338:Everolimus; D020123:Sirolimus; D000077205:Pioglitazone
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