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

doi:10.1073/pnas.0437967100

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

^*Laboratory of Genomic Biology, Institut National de la Santé et de la Recherche Médicale–Avenir Group and Fondation Jean Dausset–Centre d'Etude du Polymorphisme Humain, 75010 Paris, France; ^†Bedford Veterans Administration Medical Center, Bedford, MA 01730; ^‡Departments of Neurology, Pathology, and Psychiatry, Boston University School of Medicine, Boston, MA 01730; and ^§Unité Mixte de Recherche 146, Centre National de la Recherche Scientifique/Institut Curie, 91405 Orsay, France

Communicated by Jean Dausset, Fondation Jean Dausset–Centre d'Etude du Polymorphisme Humain, Paris, France (received for review November 13, 2002)

Abstract

Huntington's disease (HD) is a neurodegenerative disease caused by polyglutamine (polyQ) expansion in the protein huntingtin (htt). Pathogenesis in HD seems to involve the formation of neuronal intranuclear inclusions and the abnormal regulation of transcription and signal transduction. To identify previously uncharacterized 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 SH3 domain protein (K08E3.3b) that interacts with N-terminal htt in two-hybrid tests. A human homolog of K08E3.3b is the Cdc42-interacting protein 4 (CIP4), a protein involved in Cdc42 and Wiskott–Aldrich syndrome protein-dependent signal transduction. CIP4 interacted in vitro with full-length htt from lymphoblastoid cells. Neuronal CIP4 immunoreactivity increased with neuropathological severity in the neostriatum of HD patients and partially colocalized to ubiquitin-positive aggregates. Marked CIP4 overexpression also was observed in Western blot from human HD brain striatum. The overexpression of CIP4 induced the death of striatal neurons. Our data suggest that CIP4 accumulation and cellular toxicity may have a role in HD pathogenesis.

Footnotes

↵ ¶ To whom correspondence should be addressed at: Laboratory of Genomic Biology, Centre d'Etude du Polymorphisme Humain, 27 Rue Juliette Dodu, 75010 Paris, France. E-mail: neri{at}cephb.fr.
Abbreviations:

CIP4,

Cdc42-interacting protein 4;

HD,

Huntington's disease;

htt,

huntingtin;

polyQ,

polyglutamine;

WASP,

Wiskott–Aldrich syndrome protein