Abstract
AbstractScrapie is an infective ovine neurodegenerative disease; the only identified component of the infectious agent being an aberrant isoform (PrPSc) of the cellular prion protein (PrPC). So far, no means for ante-mortem diagnosis are available for Scrapie as well as for any other mammal Transmissible Spongiform Encephalopaties. We recently found a strong relationship between cell susceptibility to scrapie-infection and intracellular cholesterol homeostasis alterations. In brain tissues as well as in ex vivo cultures of skin fibroblasts and PBMCs from healthy and scrapie-affected sheep carrying a scrapie-susceptible (ARQ/ARQ) genotype, the levels of cholesterol esters were consistently higher than in tissues and cultures derived from animals with a scrapie-resistant (ARR/ARR) genotype. Moreover, both uninfected and scrapie-affected ARQ/ARQ sheep showed abnormally low levels of high density lipoprotein-cholesterol (HDL-C) in their plasma, as compared to ARR/ARR animals. We now show that intracellular accumulation of cholesterol esters in fibroblasts derived from scrapie-susceptible sheep was accompanied by parallel alterations in the expression level of genes and gene products (ACAT1 and Cav-1) that are involved in the pathways leading to intracellular cholesterol esterification and trafficking. Comparative analysis of PrPc mRNA, showed an higher expression level in cells from animals carrying susceptible genotype, with or without Scrapie. Preliminary experiments also revealed the presence of PK-resistant PrP isoforms in the latter cultures. The data reported in the present paper suggest that accumulation of cholesterol esters in peripheral cells, together with the altered expression of some proteins implicated in intracellular cholesterol homeostasis, might serve to identify a distinctive lipid metabolic profile associated with increased susceptibility to develop prion disease following infection.
Highlights
Prion diseases are fatal neurodegenerative disorders for which no “in vitam” diagnostic tests nor effective treatments are currently available
PrPSc is generally thought to represent the infectious agent of Scrapie, through its ability to promote the structural conversion of the normal cellular prion protein PrPc into a likeness of itself[16]
We found that cellular cholesterol alterations were accompanied by parallel alterations in the expression levels of genes and gene products, ACAT1 and Cav-1, involved in the pathways leading to intracellular cholesterol esterification and trafficking
Summary
Prion diseases are fatal neurodegenerative disorders for which no “in vitam” diagnostic tests nor effective treatments are currently available. PrPc is normally GPI-anchored to specialized cholesterol-rich domains of the plasma membrane, termed lipid rafts or caveolae[2]. These membrane domains are detergent-insoluble regions characterized by the presence of free cholesterol (FC), saturated phospholipids and raft-resident proteins [3]. [5,6,7] In normal tissues, approximately 90% of the total cellular cholesterol resides in membrane raft domains as FC, while only a minor amount (approximately 1-10%) is found as cholesterol esters (CE) in a cytoplasmic storage form [8]. Because membrane cholesterol appears critical for the function of raft-resident proteins, cells developed a highly integrated set of homeostatic mechanisms that finely regulate FC vs CE pools according to the cell’s need. Similar alterations were observed in mouse neuroblastoma cell lines persistently infected with mouseadapted 22L and RML strains of scrapie that showed up to 3-fold higher CE levels than parental
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