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

Shankaran, Mahalakshmi, Di Paolo, Eleonora, Leoni, Valerio, Caccia, Claudio, Ferrari Bardile, Costanza, Mohammed, Hussein, Di Donato, Stefano, Kwak, Seung, Marchionini, Deanna, Turner, Scott, Cattaneo, Elena, Valenza, Marta·2017·Neurobiology of Disease
DOI 10.1016/j.nbd.2016.11.013
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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 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.

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  • The reduction in cholesterol biosynthesis in HD mouse brain is CAG-dependent.

    “In the adult HD mouse brain, this dysfunction is evidenced by a reduced rate of de novo cholesterol biosynthesis, precedes the onset of motor symptoms, is CAG-dependent, as confirmed by studies in an allelic series of HD mice, and leads to a reduced content of total cholesterol (and of some of its metabolites and catabolites) at late symptomatic stages 21 .”

    From SREBP2 gene therapy targeting striatal astrocytes ameliorates Huntington’s disease phenotypes (2021) · cites this paper as [21]

  • Cholesterol biosynthesis is severely reduced in the brain of HD mouse models, with the striatum affected first.

    “A large number of studies conducted in different HD rodent models have demonstrated significantly reduced biosynthesis of cholesterol in the brain, with the striatum being affected first 17,18,19,20,21 .”

    From SREBP2 gene therapy targeting striatal astrocytes ameliorates Huntington’s disease phenotypes (2021) · cites this paper as [21]

  • The reduction in cholesterol biosynthesis in HD mouse brain precedes the onset of motor symptoms.

    “In the adult HD mouse brain, this dysfunction is evidenced by a reduced rate of de novo cholesterol biosynthesis, precedes the onset of motor symptoms, is CAG-dependent, as confirmed by studies in an allelic series of HD mice, and leads to a reduced content of total cholesterol (and of some of its metabolites and catabolites) at late symptomatic stages 21 .”

    From SREBP2 gene therapy targeting striatal astrocytes ameliorates Huntington’s disease phenotypes (2021) · cites this paper as [21]

  • In adult HD mouse brain, the rate of de novo cholesterol biosynthesis is reduced.

    “In the adult HD mouse brain, this dysfunction is evidenced by a reduced rate of de novo cholesterol biosynthesis, precedes the onset of motor symptoms, is CAG-dependent, as confirmed by studies in an allelic series of HD mice, and leads to a reduced content of total cholesterol (and of some of its metabolites and catabolites) at late symptomatic stages 21 .”

    From SREBP2 gene therapy targeting striatal astrocytes ameliorates Huntington’s disease phenotypes (2021) · cites this paper as [21]

  • The reduction in cholesterol biosynthesis in HD mouse brain leads to reduced total cholesterol at late symptomatic stages.

    “In the adult HD mouse brain, this dysfunction is evidenced by a reduced rate of de novo cholesterol biosynthesis, precedes the onset of motor symptoms, is CAG-dependent, as confirmed by studies in an allelic series of HD mice, and leads to a reduced content of total cholesterol (and of some of its metabolites and catabolites) at late symptomatic stages 21 .”

    From SREBP2 gene therapy targeting striatal astrocytes ameliorates Huntington’s disease phenotypes (2021) · cites this paper as [21]

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Metadata

Authors
Shankaran, M., Di Paolo, E., Leoni, V., Caccia, C., Ferrari Bardile, C., Mohammed, H., Di Donato, S., Kwak, S., Marchionini, D., Turner, S., Cattaneo, E., & Valenza, M.
ORCID
Valenza, Marta
Venue
Neurobiology of Disease
Publisher
Elsevier BV
Published
2017-02
Volume
98
Pages
66-76
ISSN
0969-9961
DOI
10.1016/j.nbd.2016.11.013
Cited by
54
References
0
Language
en
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Funders
CHDI Foundation (A-5086, A-5142, GR-2008)

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