Do Prion-Induced Changes in Membrane Cholesterol Trigger Neurodegeneration?

Abstract

The transmissible spongiform encephalopathies (TSEs) are associated with the conversion of a host-encoded cellular protein (PrPC) to alternatively folded, disease-associated isoforms (PrPSc) [1]. These diseases are unique in that the only identified component of the infectious agent is a self-replicating protein (PrPSc); which explains why such diseases are commonly called prion diseases (protein-only infectious agent). The accumulation of PrPSc is closely associated with the main pathological features of prion diseases; loss of synapses, activation of glial cells, neuronal loss and the spongiform degeneration of the brain [2]. However, the cellular and molecular mechanisms leading to neurodegeneration in these diseases are imperfectly understood. In this review, we outline developments implicating prion-induced changes in the levels of membrane cholesterol as a trigger of abnormal cell signaling, which leads to neurodegeneration. Recent studies have demonstrated that prion infection has a significant impact on the biochemistry of neuronal cell membranes; it significantly increased the amounts of free cholesterol, but reduced the amounts of esterified cholesterol [3]. In addition, a highly significant correlation between the amounts of PrPSc and the concentration of free cholesterol in cell membranes was observed. Crucially, the effects of prion infection were not replicated by stimulating cholesterol biosynthesis. Stimulation of cholesterol production in uninfected neurons had the opposite effect to prion infection; it increased cholesterol ester formation without altering the amounts of free cholesterol. Such observations indicate that prion infection increased the capacity of cell membranes to solubilize free cholesterol. Cellular cholesterol is found as either free cholesterol in membranes, or as cholesterol esters that are stored in cytoplasmic droplets. A dynamic equilibrium between the pools of free cholesterol and cholesterol esters is tightly controlled by acyl-coenzyme A:cholesterol acyltransferase (ACAT), an endoplasmic reticulum (ER)-resident enzyme that esterifies free cholesterol with long-chain fatty acids [4]. Therefore, the combination of increased free cholesterol and reduced cholesterol esters observed in prion-infected cells may result from inhibition of ACAT, or from the sequestration of free cholesterol in microenvironments that avoid ACAT.