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Progressive dysfunction of the cholesterol biosynthesis pathway in the R6/2 mouse model of Huntington’s disease

Valenza, Marta, Leoni, Valerio, Tarditi, Alessia, Mariotti, Caterina, Björkhem, Ingeman, Di Donato, Stefano, Cattaneo, Elena·2007·Neurobiology of Disease
DOI 10.1016/j.nbd.2007.07.004
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Abstract

We have recently reported significantly reduced levels of the mRNA of genes critical for the cholesterol biosynthesis pathway in the brains of mice and patients with Huntington's disease (HD), which are indicative of a biological dysfunction. We here show that the brains of R6/2 transgenic mice have progressively decreasing levels of the cholesterol precursors, lathosterol and lanosterol, and declining 3-hydroxy-3-methylglutaryl coenzyme A reductase activity starting from pre-symptomatic stages. We also show that, despite the progressive reduction of brain cholesterol biosynthesis, steady-state levels of total cholesterol remain constant, thus suggesting that compensatory mechanisms are in operation. These in vivo findings indicate a consistent and progressive reduction in the activity of the cholesterol biosynthesis pathway in HD brain. The defect occurs early in these mice and generates lower levels of newly synthesized cholesterol and its intermediates, which may affect different aspects of the disease.

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  • 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 [18]

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Metadata

Authors
Valenza, M., Leoni, V., Tarditi, A., Mariotti, C., Björkhem, I., Di Donato, S., & Cattaneo, E.
Venue
Neurobiology of Disease
Publisher
Elsevier BV
Published
2007-10
Volume
28
Issue
1
Pages
133-142
ISSN
0969-9961
DOI
10.1016/j.nbd.2007.07.004
Cited by
115
References
5
Language
en
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)

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