title: Early and brain region-specific decrease of de novo cholesterol biosynthesis in Huntington's disease: A cross-validation study in Q175 knock-in mice.
abstract: Cholesterol precursors and cholesterol levels are reduced in brain regions of Huntington's disease (HD) mice. Here we quantified the rate of in vivo de novo cholesterol biosynthesis in the HD brain. Samples from different brain regions and blood of the heterozygous knock-in mouse model carrying 175 CAG repeats (Q175) at different phenotypic stages were processed independently by two research units to quantify cholesterol synthesis rate by2H2O labeling and measure the concentrations of lathosterol, cholesterol and its brain-specific cholesterol catabolite 24-hydroxy-cholesterol (24OHC) by isotope dilution mass spectrometry. The daily synthesis rate of cholesterol and the corresponding concentration of lathosterol were significantly reduced in the striatum of heterozygous Q175 mice early in the disease course. We also report that the decrease in lathosterol was inversely correlated with CAG-size at symptomatic stage, as observed in striatal samples from an allelic series of HD mice. There was also a significant correlation between the fractional synthesis rates of total cholesterol and 24OHC in brain of wild-type (WT) and Q175 mice, supporting the evidence that plasma 24OHC may reflect cholesterol synthesis in the adult brain. This comprehensive analysis demonstrates consistent cholesterol biosynthesis defects in HD mouse models and suggests that plasma 24OHC may serve as a biomarker of brain cholesterol metabolism.
authors.affiliation: KineMed Inc., Emeryville, CA 94608, USA.
authors.forename: Mahalakshmi
authors.initials: M
authors.lastname: Shankaran
authors.affiliation: Department of BioSciences and Centre for Stem Cell Research, Università degli Studi di Milano, 20122 Milan, Italy.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Di Paolo
authors.affiliation: Neurological Institute C. Besta, 20133 Milan, Italy; Laboratory of Clinical Chemistry, Hospital of Varese, 21010 Varese, Italy.
authors.forename: Valerio
authors.initials: V
authors.lastname: Leoni
authors.affiliation: Neurological Institute C. Besta, 20133 Milan, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Caccia
authors.affiliation: Department of BioSciences and Centre for Stem Cell Research, Università degli Studi di Milano, 20122 Milan, Italy.
authors.forename: Costanza
authors.initials: C
authors.lastname: Ferrari Bardile
authors.affiliation: KineMed Inc., Emeryville, CA 94608, USA.
authors.forename: Hussein
authors.initials: H
authors.lastname: Mohammed
authors.affiliation: Neurological Institute C. Besta, 20133 Milan, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Di Donato
authors.affiliation: CHDI Management/CHDI Foundation, 350 Seventh Ave, Suite 200, New York, NY 10001, USA.
authors.forename: Seung
authors.initials: S
authors.lastname: Kwak
authors.affiliation: CHDI Management/CHDI Foundation, 350 Seventh Ave, Suite 200, New York, NY 10001, USA.
authors.forename: Deanna
authors.initials: D
authors.lastname: Marchionini
authors.affiliation: KineMed Inc., Emeryville, CA 94608, USA.
authors.forename: Scott
authors.initials: S
authors.lastname: Turner
authors.affiliation: Department of BioSciences and Centre for Stem Cell Research, Università degli Studi di Milano, 20122 Milan, Italy. Electronic address: elena.cattaneo@unimi.it.
authors.forename: Elena
authors.initials: E
authors.lastname: Cattaneo
authors.affiliation: Department of BioSciences and Centre for Stem Cell Research, Università degli Studi di Milano, 20122 Milan, Italy. Electronic address: marta.valenza@unimi.it.
authors.forename: Marta
authors.initials: M
authors.lastname: Valenza
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000097:blood; D001921:Brain / Q000378:metabolism*; D002784:Cholesterol / Q000096:biosynthesis*; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D055879:Gene Knock-In Techniques; D006816:Huntington Disease / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D012727:Sex Characteristics
chemical_list: D015415:Biomarkers; D002784:Cholesterol
keywords: Brain cholesterol; Huntington; Lathosterol; Striatum