Human Molecular Genetics, 2002, Vol. 11, No. 8 905-914
© 2002 Oxford University Press
Huntingtin inclusions do not deplete polyglutamine-containing transcription factors in HD mice
1Department of Human Genetics, Emory University, School of Medicine, Atlanta, GA 30322, USA
A pathological hallmark of polyglutamine diseases is the presence of inclusions or aggregates of the expanded polyglutamine protein. Polyglutamine inclusions are present in the neuronal nucleus in a number of inherited neurodegenerative disorders, including Huntington disease (HD). Recent studies suggest that polyglutamine inclusions may sequester polyglutamine-containing transcription factors and deplete their concentration in the nucleus, leading to altered gene expression. To test this hypothesis, we examined the expression and localization of the polyglutamine-containing or glutamine-rich transcription factors TBP, CBP and Sp1 in HD mouse models. All three transcription factors were diffusely distributed in the nucleus, despite the presence of abundant intranuclear inclusions. There were no differences in the nuclear staining of these transcription factors between HD and wild-type mouse brains. Although some CBP staining appeared as dots in the selective brain regions (e.g. hypothalamus and amygdala), double labeling showed that most CBP was not co-localized with huntingtin nuclear inclusions. Electron microscopy confirmed that CBP was diffusely distributed in the nucleus. Western blots showed that these transcription factors were not trapped in huntingtin inclusions. In the striatum of HD mice, which suffers a significant reduction in the expression of a number of genes, mutant huntingtin was present in both an aggregated and a diffuse form. These findings suggest that altered gene expression may result from the interactions of soluble mutant huntingtin with nuclear transcription factors, rather than from the depletion of transcription factors by nuclear inclusions.
* To whom correspondence should be addressed at: Department of Human Genetics, Emory University School of Medicine, Whitehead Building 347, 615 Michael Street, Atlanta, GA 30322, USA. Tel: +1 404 727 3290; Fax: +1 404 727 3949; Email: xiaoli{at}genetics.emory.edu
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