Abnormalities of cholesterol metabolism in multiple system atrophy

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Summary Multiple system atrophy, or MSA, is the most common cause of adult-onset neurodegenerative ataxia, and so far, no disease-modifying therapy has been developed. One of the reasons for this lack of therapy is that the etiology of MSA remains unclear, though several possible mechanisms have been proposed. Defects in the synthesis and levels of Coenzyme Q (ubiquinone, CoQ), a lipophillic molecule present in virtually all cell membranes, represent a common phenomenon in MSA, with or without mutations in the COQ2 gene, which encodes 4-para-hydroxybenzoate polyprenyl transferase, the second enzyme involved in CoQ10 biosynthesis. The essential role of CoQ in mitochondrial oxidative phosphorylation has been explored in the context of neurodegenerative disease such as MSA. However, other aspects of CoQ biology, such as its role in the regulation of cholesterol metabolism, have not been investigated. Cholesterol homeostasis is maintained in the cell by a tightly-regulated balance between its de novo synthesis, and its internalization from extracellular lipoproteins. Alterations in this balance result in neuronal dysfunction. The biosynthesis of cholesterol and CoQ are two co-regulated branches of the mevalonate pathway. As such, stimulation of cholesterol biosynthesis also results in increases in CoQ production; thus, decrease in CoQ levels should result in the subsequent activation of the mevalonate pathway and the de novo synthesis of cholesterol, followed by inhibition of the internalization of extracellular cholesterol, to maintain homeostasis. We propose that defects in CoQ biosynthesis induce cell dysfunction by alterations in cholesterol homeostasis via sustained downregulation of cholesterol internalization (AIM 1). Our published data showed that decrease in the internalization of cholesterol, but not its synthesis, results in defects in the formation of mitochondria-associated ER membranes (MAM) domains, an ER lipid-raft involved in the modulation of multiple metabolic pathways, including the regulation of lipid homeostasis. Notably, defects in the formation of MAM domains have been observed in neurodegenerative diseases such as AD, PD and ALS. Recently, CoQ synthesis has been shown to be regulated at MAM domains in yeast. However, whether this is also the case in human cells it not known. Based on our preliminary data, we propose a novel mechanism by which CoQ defects, via inhibition of cholesterol internalization, impair the formation of MAM domains and the inhibition of the activities localized in this domain (AIM 2). Our results will elucidate the interplay between CoQ, cholesterol metabolism and MAM function, and its contribution to neuronal demise in MSA, and other neurodegenerative diseases.