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Cholesterol transporter ATP-binding cassette A1 (ABCA1) is elevated in prion disease and affects PrP^C and PrP^Sc concentrations in cultured cells

McLaughlin Research Institute, Great Falls, MT 59405, USA

Correspondence
Rajeev Kumar
kumar{at}po.mri.montana.edu
George A. Carlson
gac{at}po.mri.montana.edu

Prion diseases are transmissible neurodegenerative disorders of prion protein (PrP) conformation. Prion replication by conversion of benign PrP^C isoforms into disease-specific PrP^Sc isoforms is intimately involved in prion disease pathogenesis and may be initiated in cholesterol-rich caveolae-like domains (CLD). Concentrations of the cholesterol transporter ATP-binding cassette A1 protein (ABCA1) are elevated in pre-clinical scrapie prion-infected mice and in prion-infected cells in vitro. Elevation of ABCA1 in prion-infected brain is not a direct consequence of local PrP^Sc accumulation, indeed levels of ABCA1 are comparable in brain regions that differ dramatically in the amount of PrP^Sc. Similarly, ABCA1 concentrations are identical in normal mice, transgenic mice overexpressing PrP and PrP knockout mice. In contrast, PrP^C and PrP^Sc levels, but not Prnp mRNA, were increased by overexpression of ABCA1 in N2a neuroblastoma cells and scrapie prion-infected N2a cells (ScN2a). Conversely, RNAi-mediated knock down of Abca1 expression decreased the concentrations of PrP^C in N2a cells and of PrP^Sc in ScN2a cells. These results suggest that ABCA1's effects on PrP^C levels are post-translational and may reflect an increase in of PrP^C stability, mediated either indirectly by increasing membrane cholesterol and CLD formation or by other functions of ABCA1. The increased supply of PrP^C available for conversion would lead to increased PrP^Sc formation.

Supplementary figures are available with the online version of this paper.