Prion Infection Impairs Cholesterol Metabolism in Neuronal Cells |
| |
Authors: | Huanhuan L. Cui Belinda Guo Benjamin Scicluna Bradley M. Coleman Victoria A. Lawson Laura Ellett Peter J. Meikle Michael Bukrinsky Nigora Mukhamedova Dmitri Sviridov Andrew F. Hill |
| |
Affiliation: | From the ‡Baker Heart and Diabetes Institute, Melbourne, Victoria 8008, Australia.;the §Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, and ;¶Department of Pathology, University of Melbourne, Melbourne, Victoria 3010, Australia, and ;the ‖Department of Microbiology, Immunology, and Tropical Medicine, George Washington University, Washington, D. C. 20854 |
| |
Abstract: | Conversion of prion protein (PrPC) into a pathological isoform (PrPSc) during prion infection occurs in lipid rafts and is dependent on cholesterol. Here, we show that prion infection increases the abundance of cholesterol transporter, ATP-binding cassette transporter type A1 (ATP-binding cassette transporter type A1), but reduces cholesterol efflux from neuronal cells leading to the accumulation of cellular cholesterol. Increased abundance of ABCA1 in prion disease was confirmed in prion-infected mice. Mechanistically, conversion of PrPC to the pathological isoform led to PrPSc accumulation in rafts, displacement of ABCA1 from rafts and the cell surface, and enhanced internalization of ABCA1. These effects were abolished with reversal of prion infection or by loading cells with cholesterol. Stimulation of ABCA1 expression with liver X receptor agonist or overexpression of heterologous ABCA1 reduced the conversion of prion protein into the pathological form upon infection. These findings demonstrate a reciprocal connection between prion infection and cellular cholesterol metabolism, which plays an important role in the pathogenesis of prion infection in neuronal cells. |
| |
Keywords: | ABC Transporter Cholesterol Lipid Raft Neurodegenerative Diseases Prions |
|
|