The Gln-Ala repeat transcriptional activator CA150 interacts with huntingtin: Neuropathologic and genetic evidence for a role in Huntington's disease pathogenesis

Abstract

Huntington's disease (HD) is a neurodegenerative disease caused by polyglutamine expansion in the protein huntingtin (htt). Pathogenesis in HD appears to involve the formation of ubiquitinated neuronal intranuclear inclusions containing N-terminal mutated htt, abnormal protein interactions, and the aggregate sequestration of a variety of proteins (noticeably, transcription factors). To identify novel htt-interacting proteins in a simple model system, we used a yeast two-hybrid screen with a Caenorhabditis elegans activation domain library. We found a predicted WW domain protein (ZK1127.9) that interacts with N-terminal fragments of htt in two-hybrid tests. A human homologue of ZK1127.9 is CA150, a transcriptional coactivator with a N-terminal insertion that contains an imperfect (Gln-Ala)38 tract encoded by a polymorphic repeat DNA. CA150 interacted in vitro with full-length htt from lymphoblastoid cells. The expression of CA150, measured immunohistochemically, was markedly increased in human HD brain tissue compared with normal age-matched human brain tissue, and CA150 showed aggregate formation with partial colocalization to ubiquitin-positive aggregates. In 432 HD patients, the CA150 repeat length explains a small, but statistically significant, amount of the variability in the onset age. Our data suggest that abnormal expression of CA150, mediated by interaction with polyglutamineexpanded htt, may alter transcription and have a role in HD pathogenesis.

Effects of intracellular expression of anti-huntingtin antibodies of various specificities on mutant huntingtin aggregation and toxicity

“…A potential mechanism contributing to HD pathogenesis is the recruitment of WW-rich proteins. In fact, several WW-containing proteins, including CA150, spliceosomes, and transcription factors, can interact with htt exon 1 (20)(21)(22). Moreover, interaction of some of the WW proteins with htt exon 1 is enhanced in htt with an expanded polyQ stretch (20,21).…”

“…Several proteins that interact with exon 1 of htt have been identified (14,(18)(19)(20)(21)(22)(23), and although the function of these proteins in the etiology of HD is unclear, the transcriptional coactivator CREB-binding protein (CBP) as well as proteins with WW domains have been implicated in the HD pathology (18)(19)(20)(21). Binding of htt to CBP has been shown to repress CBP-mediated gene expression (18,19).…”

Modèles animaux des maladies neuro-dégénératives

“…De son côté, le nématode Caenorhabditis elegans est facile à entretenir et à conserver congelé, et le lignage des cellules qui le composent est entièrement connu. Il a été utilisé pour rechercher les partenaires de la Huntingtine [53] et pour cribler des molécules à intérêt thérapeutique potentiel [54] dans la chorée de Huntington. Enfin, le poisson-zèbre, où la transgenèse est facile à réaliser, pourrait constituer un modèle intéressant : il a encore été peu utilisé dans l'étude de la neurodégé-nérescence.…”

Cdc42-interacting protein 4 binds to huntingtin: Neuropathologic and biological evidence for a role in Huntington's disease

“…Bound proteins were eluted from the beads, separated by SDS͞PAGE, and analyzed by Western blotting using a mAb specific to htt (HU-4C8; 1:2,500; Euromedex, Mundolsheim, France). The CAG repeat size in the htt gene of the individuals tested was determined as described (28 4 -20 h) and were similar for controls and HD patients. CAG repeat length analysis was performed in all of the HD cases (14͞14).…”