Journal Article

Aberrant Interactions of Transcriptional Repressor Proteins with the Huntington's Disease Gene Product, Huntingtin

Jonathan M. Boutell, Philip Thomas, James W. Neal, Victoria J. Weston, James Duce, Peter S. Harper and A. Lesley Jones

in Human Molecular Genetics

Volume 8, issue 9, pages 1647-1655
Published in print September 1999 | ISSN: 0964-6906
Published online September 1999 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/8.9.1647
Aberrant Interactions of Transcriptional Repressor Proteins with the Huntington's Disease Gene Product, Huntingtin

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We detected an interaction of the N-terminus of huntingtin (htt171) with the C-terminal region of the nuclear receptor co-repressor (N-CoR) using the yeast two-hybrid system. This interaction was repeat length dependent and specific to htt171; the co-repressor did not interact with the repeat carrying a section of atrophin 1 nor with the androgen receptor or polyglutamine alone. The interaction was confirmed using His-tagged Escherichia coli-expressed C-terminal human and rat co-repressor protein which pulled full-length huntingtin out of homogenized rat brain and in pull-down assays. The N-CoR represses transcription from sequence-specific ligand-activated receptors such as the retinoid X-thyroid hormone receptor dimers and other nuclear receptors including Mad-Max receptor dimers. The mechanism of this repression appears to be through the formation of a complex of repressor proteins including the N-CoR, mSin3 and histone deacetylases. We have used N-CoR and mSin3A antibodies in immunohisto-chemical studies and find that in Huntington's disease (HD) cortex and caudate, the cellular localization of these proteins is exclusively cytoplasmic whilst in control brain they are localized in the nucleus as well as the cytoplasm; mSin3A immuno-reactivity also occurred in a subset of huntingtin positive intranuclear inclusions. The relocalization of repressor proteins in HD brain may alter transcription and be involved in the pathology of the disease.

Journal Article.  7018 words.  Illustrated.

Subjects: Genetics and Genomics

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