Dysfunction of the Cholesterol Biosynthetic Pathway in Huntington's Disease

The expansion of a polyglutamine tract in the ubiquitously expressed huntingtin protein causes Huntington’s disease (HD), a dominantly
inherited neurodegenerative disease.Weshow that the activity of the cholesterol biosynthetic pathway is altered in HD. In particular, the
transcription of key genes of the cholesterol biosynthetic pathway is severely affected in vivo in brain tissue from HD mice and in human
postmortem striatal and cortical tissue; this molecular dysfunction is biologically relevant because cholesterol biosynthesis is reduced in
cultured human HD cells, and total cholesterol mass is significantly decreased in the CNS of HD mice and in brain-derived ST14A cells in
which the expression of mutant huntingtin has been turned on. The transcription of the genes of the cholesterol biosynthetic pathway is
regulated via the activity of sterol regulatory element-binding proteins (SREBPs), and we found an50% reduction in the amount of the
active nuclear form of SREBP in HD cells and mouse brain tissue. As a consequence, mutant huntingtin reduces the transactivation of an
SRE–luciferase construct even under conditions of SREBP overexpression or in the presence of an exogenous N-terminal active form of
SREBP. Finally, the addition of exogenous cholesterol to striatal neurons expressing mutant huntingtin prevents their death in a dosedependent
manner. We conclude that the cholesterol biosynthetic pathway is impaired in HD cells, mice, and human subjects, and that
the search for HD therapies should also consider cholesterol levels as both a potential target and disease biomarker.