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Human Molecular Genetics, 2002, Vol. 11, No. 17 1953-1965
© 2002 Oxford University Press

Early transcriptional profiles in huntingtin-inducible striatal cells by microarray analyses

Simonetta Sipione1,{dagger}, Dorotea Rigamonti1,{dagger}, Marta Valenza1, Chiara Zuccato1, Luciano Conti1, Joel Pritchard2, Charles Kooperberg3, James M. Olson2 and Elena Cattaneo1,*

1Department of Pharmacological Sciences and Center of Excellence on Neurodegenerative Diseases, University of Milano, Via Balzaretti 9, 20133 Milano, Italy and 2Clinical Research Division and 3Public Health Science Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA

Received March 12, 2002; Accepted June 3, 2002

Gene expression studies conducted with mouse models of Huntington's disease (HD) have revealed profound modifications in gene transcription. However, the complexity of in vivo tissue hampers definition of very early transcriptional modifications and does not allow discrimination between cell-autonomous changes and those resulting from intercellular activity processes. To identify early, cell-autonomous transcriptional changes, we compared gene expression profiles of clonal striata-derived cells expressing different N-terminal 548-amino-acid huntingtin fragments (with 26, 67, 105 or 118 glutamines) under the control of a doxycycline-regulated promoter. In these cells, mutant huntingtin did not form aggregates or cause cell death; therefore, the gene expression profiles report transcriptional changes reflecting early pathogenic events. We found that genes involved in cell signaling, transcription, lipid metabolism and vesicle trafficking were affected, in some cases, within 12 hours of mutant protein induction. Interestingly, this study revealed differential expression of a number of genes involved in cholesterol and fatty acid metabolism, suggesting that these metabolic pathways may play a role in HD pathogenesis.

* To whom correspondence should be addressed. Tel: +39 0250318333/349; Fax: +39 0250318284; Email: elena.cattaneo{at}unimi.it

{dagger} The author wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.


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