Abstract

Our recent analyses of the cholesterol biosynthetic pathway in Huntington's disease (HD) cells, in the R6/2 huntingtin-fragment mouse model of HD as well as in human tissues have provided the first evidence of altered activity of this pathway in genetically identifiable HD samples. Here we report that these changes also occur in the full-length-huntingtin YAC128 (yeast artificial chromosome) mouse model, which shows a consistent reduction in the activity or levels of multiple components of the cholesterogenic pathway. We also show that this phenotype is progressive and is specific for the brain region most affected in HD. Mice over-expressing the wild-type protein with 18 CAG (YAC18 mice) show the opposite phenotype with higher activity of the cholesterol biosynthetic pathway compared with littermate mice. Finally, we report that plasma levels of cholesterol, its precursors and its brain-derived catabolite 24-S-hydroxycholesterol in YAC mice mirror brain biosynthetic levels supporting further investigation of their potential as peripheral biomarkers in HD.