The Gln-Ala repeat transcriptional activator CA150 interacts with huntingtin: neuropathologic and genetic evidence for a role in Huntington's disease pathogenesis.
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 polyglutamine-expanded htt, may alter transcription and have a role in HD pathogenesis.
Holbert
S
S
Laboratory of Genomic Biology, Fondation Jean Dausset, Centre d'Etude du Polymorphisme Humain, 75010 Paris, France.
Denghien
I
I
Kiechle
T
T
Rosenblatt
A
A
Wellington
C
C
Hayden
M R
MR
Margolis
R L
RL
Ross
C A
CA
Dausset
J
J
Ferrante
R J
RJ
Néri
C
C
D017668:Age of Onset; D000409:Alanine; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D017173:Caenorhabditis elegans; D018900:Dinucleotide Repeats; D005973:Glutamine; D015801:Helminth Proteins / Q000235:genetics / Q000378:metabolism; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D035602:Transcriptional Elongation Factors
C086055:HTT protein, human; D015801:Helminth Proteins; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D011993:Recombinant Fusion Proteins; C108440:TCERG1 protein, human; D015534:Trans-Activators; D035602:Transcriptional Elongation Factors; D005973:Glutamine; D000409:Alanine