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

Abstract

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 immunohistochemical 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 immunoreactivity 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.

Huntingtin protein interactions altered by polyglutamine expansion as determined by quantitative proteomic analysis

“…Interestingly, mSin3A immunoreactivity was previously observed in Htt-positive intranuclear inclusions. 18 As shown in Figure 2A, Htt-50Q preferential interactors were more enriched in proteins related to RNA post-transcriptional modifications. Twenty-eight proteins related to RNA processing and regulation of translation were identified as preferential interactors of Htt-50Q (Table S1).…”

Ataxin 1, a SCA1 neurodegenerative disorder protein, is functionally linked to the silencing mediator of retinoid and thyroid hormone receptors

“…For example, huntingtin (Htt) interacts with nuclear receptor corepressor and Sin3A (37,38); atrophin-1 recruits Sin3A and HDAC2 in transfected cells (39); and androgen receptor, a nuclear receptor itself, was recently found to interact with SMRT as well (40,41). It is thus becoming evident that certain aspects of polyglutamine-protein functions are mediated through transcriptional corepressors.…”

Mutant huntingtin can paradoxically protect neurons from death

“…[29][30][31][32][33] Other candidates that possibly could interact with the domain of the protein encoded by exon 1, but have not been shown to interact only with this short sequence, include huntingtin interacting protein 1 (HIP1), Rab11 familyinteracting protein 2 (FIP2), huntingtin interacting protein 14 (HIP14), nuclear receptor corepressor 1 (N-CoR) and cystathionine beta-synthase (CBS) [34][35][36][37][38] (for overview see Figure 2). …”