Plasma cholesterol level determines in vivo prion propagation

Abstract : Transmissible spongiform encephalopathies (TSE) are fatal neurodegenerative diseases with an urgent need for therapeutic and prophylactic strategies. At the time when the blood-mediated transmission of prions was demonstrated, in vitro studies indicated a high binding affinity of the scrapie prion protein (PrPSc) with apolipoprotein B-containing lipoproteins, i.e. the main carriers of cholesterol in human blood. The aim of the present study was to explore the relationship between circulating cholesterol-containing lipoproteins and the pathogenicity of prions in vivo. We showed that in mice with a genetically-engineered deficiency for the plasma lipid transporter phospholipid transfer protein (PLTP), abnormally low circulating cholesterol concentrations were associated with a significant prolongation of survival time after intraperitoneal inoculation of the 22L prion strain. Moreover, when circulating cholesterol levels rose after feeding PLTP-deficient mice a lipid-enriched diet, a significant reduction in survival time of mice together with a marked increase in the accumulation rate of PrPSc deposits in their brain were observed. Our results suggest that the circulating cholesterol level is a determinant of prion propagation in vivo, and that cholesterol lowering strategies might be a successful therapeutic approach for patients suffering from prion diseases. Copyright © 2017, The American Society for Biochemistry and Molecular Biology.
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Soumis le : samedi 30 septembre 2017 - 11:49:18
Dernière modification le : jeudi 4 juillet 2019 - 11:38:06

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Véronique Perrier, Thibaut Imberdis, Pierre-André Lafon, Marina Cefis, Yunyun Wang, et al.. Plasma cholesterol level determines in vivo prion propagation. Journal of Lipid Research, American Society for Biochemistry and Molecular Biology, 2017, 58, pp.1950-1961. ⟨http://www.jlr.org/content/early/2017/08/02/jlr.M073718.long⟩. ⟨10.1194/jlr.M073718⟩. ⟨hal-01598901⟩

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