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The Gln-Ala repeat transcriptional activator CA150 interacts with huntingtin: neuropathologic and genetic evidence

S Holbert1, I Denghien, T Kiechle

  • 1Laboratory of Genomic Biology, Fondation Jean Dausset, Centre d'Etude du Polymorphisme Humain, 75010 Paris, France.

Proceedings of the National Academy of Sciences of the United States of America
|February 15, 2001
PubMed

Insights

Huntington's disease (HD) involves huntingtin protein (htt) aggregation. Researchers identified CA150, a protein that interacts with mutated htt, potentially contributing to HD pathogenesis and disease onset variability.

Area of Science:

  • Neuroscience
  • Genetics
  • Molecular Biology

Background:

  • Huntington's disease (HD) is a neurodegenerative disorder characterized by polyglutamine expansion in the huntingtin protein (htt).
  • HD pathogenesis involves htt aggregation, formation of neuronal intranuclear inclusions, and altered protein interactions, notably with transcription factors.

Purpose of the Study:

  • To identify novel huntingtin-interacting proteins using a yeast two-hybrid screen in a simple model system.
  • To investigate the role of the identified interacting protein, CA150, in Huntington's disease pathogenesis.

Main Methods:

  • Yeast two-hybrid screen using a Caenorhabditis elegans activation domain library to identify htt-interacting proteins.
  • In vitro interaction assays, immunohistochemistry on human brain tissue, and analysis of CA150 repeat length in HD patients.

Main Results:

  • A WW domain protein (ZK1127.9) interacting with htt fragments was identified; its human homologue is CA150.
  • CA150 expression is significantly increased in HD brain tissue and forms aggregates, partially colocalizing with ubiquitin.
  • CA150 repeat length correlates with a small but significant portion of the variability in HD onset age.

Conclusions:

  • CA150 interacts with polyglutamine-expanded huntingtin protein.
  • Abnormal CA150 expression and its interaction with htt may play a role in Huntington's disease pathogenesis by altering transcription.

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