RT Journal Article
SR Electronic
T1 Dysfunction of the Cholesterol Biosynthetic Pathway in Huntington's Disease
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 9932
OP 9939
DO 10.1523/JNEUROSCI.3355-05.2005
VO 25
IS 43
A1 Marta Valenza
A1 Dorotea Rigamonti
A1 Donato Goffredo
A1 Chiara Zuccato
A1 Simone Fenu
A1 Laure Jamot
A1 Andrew Strand
A1 Alessia Tarditi
A1 Ben Woodman
A1 Marco Racchi
A1 Caterina Mariotti
A1 Stefano Di Donato
A1 Alberto Corsini
A1 Gillian Bates
A1 Rebecca Pruss
A1 James M. Olson
A1 Simonetta Sipione
A1 Marzia Tartari
A1 Elena Cattaneo
YR 2005
UL http://www.jneurosci.org/content/25/43/9932.abstract
AB The expansion of a polyglutamine tract in the ubiquitously expressed huntingtin protein causes Huntington's disease (HD), a dominantly inherited neurodegenerative disease. We show 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 an ∼50% 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 dose-dependent 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.