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

Marta Valenza, Valerio Leoni, Alessia Tarditi, Caterina Mariotti, Ingeman Björkhem, Stefano Di Donato, Elena Cattaneo

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)133-142
Number of pages10
JournalNeurobiology of Disease
Volume28
Issue number1
DOIs
Publication statusPublished - Oct 2007

ASJC Scopus subject areas

  • Neurology

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