title: The impairment of cholesterol metabolism in Huntington disease.
abstract: Huntington disease (HD), an autosomal dominant neurodegenerative disorder caused by an abnormal expansion of CAG trinucleotide repeat in the Huntingtin (HTT) gene, is characterized by extensive neurodegeneration of striatum and cortex and severe diffuse atrophy at MRI. The expression of genes involved in the cholesterol biosynthetic pathway and the amount of cholesterol, lanosterol, lathosterol and 24S-hydroxycholesterol were reduced in murine models of HD. In case of HD-patients, the decrease of plasma 24OHC follows disease progression proportionally to motor and neuropsychiatric dysfunction and MRI brain atrophy, together with lanosterol and lathosterol (markers of cholesterol synthesis), and 27-hydroxycholesterol. A significant reduction of total plasma cholesterol was observed only in advanced stages. It is likely that mutant HTT decreases the maturation of SREBP and the up-regulation LXR and LXR-targeted genes (SREBP, ABCG1 and ABCG4, HMGCoA reductase, ApoE) resulting into a lower synthesis and transport of cholesterol from astrocytes to neurons via ApoE. In primary oligodendrocytes, mutant HTT inhibited the regulatory effect of PGC1α on cholesterol metabolism and on the expression of MBP. HTT seems to play a regulatory role in lipid metabolism. The impairment of the cholesterol metabolism was found to be proportional to the CAG repeat length and to the load of mutant HTT. A dysregulation on PGC1α and mitochondria dysfunction may be involved in an overall reduction of acetyl-CoA and ATP synthesis, contributing to the cerebral and whole body cholesterol impairment. This article is part of a Special Issue entitled Brain Lipids.
authors.affiliation: Laboratory of Clinical Chemistry, Ospedale Causa Pia Luvini, Cittiglio, AO Ospedale di Circolo e Fondazione Macchi, Varese, Italy; Laboratory of Clinical Pathology and Medical Genetics, Foundation IRCCS Institute of Neurology Carlo Besta, Milano, Italy. Electronic address: valerioleoni@hotmail.com.
authors.forename: Valerio
authors.initials: V
authors.lastname: Leoni
authors.affiliation: Laboratory of Clinical Pathology and Medical Genetics, Foundation IRCCS Institute of Neurology Carlo Besta, Milano, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Caccia
mesh_terms: D000818:Animals; D002540:Cerebral Cortex / Q000378:metabolism* / Q000473:pathology; D002784:Cholesterol / Q000378:metabolism*; D003342:Corpus Striatum / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006888:Hydroxycholesterols / Q000378:metabolism; D007810:Lanosterol / Q000378:metabolism; D000071518:Liver X Receptors; D051379:Mice; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D057093:Orphan Nuclear Receptors / Q000235:genetics / Q000378:metabolism; D051779:Sterol Regulatory Element Binding Proteins / Q000235:genetics / Q000378:metabolism; D018911:Trinucleotide Repeats
chemical_list: C086055:HTT protein, human; D000071058:Huntingtin Protein; D006888:Hydroxycholesterols; D000071518:Liver X Receptors; D009419:Nerve Tissue Proteins; D057093:Orphan Nuclear Receptors; D051779:Sterol Regulatory Element Binding Proteins; D007810:Lanosterol; C044563:24-hydroxycholesterol; C001521:lathosterol; D002784:Cholesterol
keywords: Biomarker; Lipid; Mass spectrometry; Metabolomics; Neurodegeneration