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The Journal of Neuroscience, April 26, 2006, 26(17):4649-4659; doi:10.1523/JNEUROSCI.5409-05.2006

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Neurobiology of Disease
CA150 Expression Delays Striatal Cell Death in Overexpression and Knock-In Conditions for Mutant Huntingtin Neurotoxicity

Margarita Arango,¹ Sébastien Holbert,¹ Dania Zala,² Emmanuel Brouillet,³ James Pearson,⁴ Etienne Régulier,² Ashwani Kumar Thakur,⁵ Patrick Aebischer,² Ronald Wetzel,⁵ Nicole Déglon,^6 * and Christian Néri^1 *

¹Institut National de la Santé et de la Recherche Médicale, Avenir Group, Laboratory of Genomic Biology, 75014 Paris, France, ²Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland, ³Department of Medical Research, Universities Research Association, Atomic Energy Commission (CEA)/Centre National de la Recherche Scientifique 2210, Service Hospitalier Frédéric Joliot and MIRCen Program, 91401 Orsay, France, ⁴Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina 27710, ⁵Graduate School of Medicine, University of Tennessee, Knoxville, Tennessee 37920, and ⁶Department of Medical Research and ImaGene Program, CEA, 91401 Orsay, France.

Correspondence should be addressed to Christian Néri, Institut National de la Santé et de la Recherche Médicale, Avenir Group, Laboratory of Genomic Biology, Centre Paul Broca, 2-ter rue d'Alésia, 75014 Paris, France. Email: neri{at}broca.inserm.fr

Transcriptional dysregulation caused by expanded polyglutamines (polyGlns) in huntingtin (htt) may be central to cell-autonomous mechanisms for neuronal cell death in Huntington's disease (HD) pathogenesis. We hypothesized that these mechanisms may involve the dysfunction of the transcriptional regulator CA150, a putative modifier of onset age in HD, because it binds to htt and accumulates in an HD grade-dependent manner in striatal and cortical neurons. Consistently, we report herein that CA150 expression rescues striatal cell death in lentiviral overexpression (rats) and knock-in (mouse cells) conditions for mutant htt neurotoxicity. In both systems, rescue was dependent on the (Gln-Ala)₃₈ repeat normally found in CA150. We excluded the possibility that rescue may be caused by the (Gln-Ala)₃₈ repeat interacting with polyGlns and, by doing so, blocking mutant htt toxicity. In contrast, we found the (Gln-Ala)₃₈ repeat is required for the nuclear restriction of exogenous CA150, suggesting that rescue requires nuclear CA150. Additionally, we found the (Gln-Ala)₃₈ repeat was dispensable for CA150 transcriptional repression ability, suggesting further that CA150 localization is critical to rescue. Finally, rescue was associated with increased neuritic aggregation, with no reduction of nuclear inclusions, suggesting the solubilization and nuclear export of mutant htt. Together, our data indicate that mutant htt may induce CA150 dysfunction in striatal neurons and suggest that the restoration of nuclear protein cooperativity may be neuroprotective.

Key words: Huntington; huntingtin; striatum; neuron death; transcription factor; neuroprotection

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Received Aug. 31, 2005; revised March 18, 2006; accepted March 20, 2006.

Correspondence should be addressed to Christian Néri, Institut National de la Santé et de la Recherche Médicale, Avenir Group, Laboratory of Genomic Biology, Centre Paul Broca, 2-ter rue d'Alésia, 75014 Paris, France. Email: neri{at}broca.inserm.fr

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