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. Copyright (copyright) 2005 Society for Neuroscience.

Dysfunction of the cholesterol biosynthetic pathway in Huntington's disease / M. Valenza, D. Rigamonti, D. Goffredo, C. Zuccato, S. Fenu, L. Jamot, A. Strand, A. Tarditi, B. Woodman, M. Racchi, C. Mariotti, S. Di Donato, A. Corsini, G. Bates, R. Pruss, J.M. Olson, S. Sipione, M. Tartari, E. Cattaneo. - In: THE JOURNAL OF NEUROSCIENCE. - ISSN 0270-6474. - 25:43(2005), pp. 9932-9939. [10.1523/JNEUROSCI.3355-05.2005]

Dysfunction of the cholesterol biosynthetic pathway in Huntington's disease

M. Valenza;D. Rigamonti;D. Goffredo;C. Zuccato;A. Tarditi;A. Corsini;M. Tartari;E. Cattaneo
2005

Abstract

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. Copyright (copyright) 2005 Society for Neuroscience.
Huntington chorea; amino terminal sequence; article; brain tissue; cell culture; cholesterol synthesis; controlled study; degenerative disease; genetic transcription; human cell; human tissue; human; priority journal; 4 aminobutyric acid receptor; cholesterol; huntingtin; sterol regulatory element binding protein
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/7710
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