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The Journal of Neuroscience, October 26, 2005, 25(43):9932-9939; doi:10.1523/JNEUROSCI.3355-05.2005

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Neurobiology of Disease
Dysfunction of the Cholesterol Biosynthetic Pathway in Huntington's Disease

Marta Valenza,^1 * Dorotea Rigamonti,^1 * Donato Goffredo,¹  Chiara Zuccato,¹  Simone Fenu,¹ Laure Jamot,² Andrew Strand,³ Alessia Tarditi,¹ Ben Woodman,⁴ Marco Racchi,⁵ Caterina Mariotti,⁶ Stefano Di Donato,⁶ Alberto Corsini,¹ Gillian Bates,⁴ Rebecca Pruss,² James M. Olson,³ Simonetta Sipione,⁷ Marzia Tartari,¹ and Elena Cattaneo¹

¹Department of Pharmacological Sciences and Center of Excellence on Neurodegenerative Diseases, University of Milan, 20133 Milan, Italy, ²Trophos, 13288 Marseille Cedex 9, France, ³Fred Hutchinson Cancer Research Center, Seattle, Washington 98109-1024, ⁴Medical and Molecular Genetics, Guy's, King's and St Thomas' School of Medicine, King's College London, Guy's Hospital, London SE1 9RT, United Kingdom, ⁵Department of Experimental and Applied Pharmacology, School of Pharmacy, University of Pavia, 27100 Pavia, Italy, ⁶Instituto di Ricovero e Cura a Carattere Scientifico, Carlo Besta Neurological Institute, 20133 Milan, Italy, and ⁷Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada T6G 2H7

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.

Key words: degeneration; GABAergic neurons; Huntington's disease; lipids; neuronal death; transcription factor

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Received June 17, 2005; revised September 17, 2005; accepted September 19, 2005.

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