Early and brain region-specific decrease of de novo cholesterol biosynthesis in Huntington's disease: A cross-validation study in Q175 knock-in mice

Mahalakshmi Shankaran, Eleonora Di Paolo, Valerio Leoni, Valerio Leoni, Claudio Caccia, Costanza Ferrari Bardile, Hussein Mohammed, Stefano Di Donato, Seung Kwak, Deanna Marchionini, Scott Turner, Elena Cattaneo, Marta Valenza

Research output: Contribution to journalArticle

Abstract

© 2016 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 by 2 H 2 O 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.
Original languageEnglish
Pages (from-to)66-76
Number of pages11
JournalNeurobiology of Disease
Volume98
DOIs
Publication statusPublished - Feb 1 2017

Keywords

  • Brain cholesterol
  • Huntington
  • Lathosterol
  • Striatum

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    Shankaran, M., Di Paolo, E., Leoni, V., Leoni, V., Caccia, C., Ferrari Bardile, C., Mohammed, H., Di Donato, S., Kwak, S., Marchionini, D., Turner, S., Cattaneo, E., & Valenza, M. (2017). Early and brain region-specific decrease of de novo cholesterol biosynthesis in Huntington's disease: A cross-validation study in Q175 knock-in mice. Neurobiology of Disease, 98, 66-76. https://doi.org/10.1016/j.nbd.2016.11.013