1887

Abstract

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

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2008-06-01
2019-11-21
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vol. 89, part 6, pp. 1525–1532

PrP concentrations increase in proportion to 8-Br-cAMP-induced expression of ABCA1.

PrP concentrations increase in proportion to 8-Br-cAMP-induced expression of ABCA1.

Levels of PrP are reduced in proportion to ABCA1 knockdown by RNAi.

Levels of PrP are reduced in proportion to ABCA1 knockdown by RNAi.

ABCA1 knockdown by RNAi reduces PrP levels.

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