title: CA150 expression delays striatal cell death in overexpression and knock-in conditions for mutant huntingtin neurotoxicity.
abstract: 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.
authors.affiliation: Avenir Group, Laboratory of Genomic Biology, Institut National de la Santé et de la Recherche Médicale, 75014 Paris, France.
authors.forename: Margarita
authors.initials: M
authors.lastname: Arango
authors.forename: Sébastien
authors.initials: S
authors.lastname: Holbert
authors.forename: Dania
authors.initials: D
authors.lastname: Zala
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Brouillet
authors.forename: James
authors.initials: J
authors.lastname: Pearson
authors.forename: Etienne
authors.initials: E
authors.lastname: Régulier
authors.forename: Ashwani Kumar
authors.initials: AK
authors.lastname: Thakur
authors.forename: Patrick
authors.initials: P
authors.lastname: Aebischer
authors.forename: Ronald
authors.initials: R
authors.lastname: Wetzel
authors.forename: Nicole
authors.initials: N
authors.lastname: Déglon
authors.forename: Christian
authors.initials: C
authors.lastname: Néri
mesh_terms: D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D003342:Corpus Striatum / Q000378:metabolism* / Q000473:pathology*; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000378:metabolism* / Q000473:pathology*; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism* / Q000473:pathology*; D009498:Neurotoxins / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014157:Transcription Factors / Q000378:metabolism*; D035602:Transcriptional Elongation Factors
chemical_list: C499524:Htt protein, rat; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009498:Neurotoxins; D009687:Nuclear Proteins; C473940:Tcerg1 protein, mouse; D014157:Transcription Factors; D035602:Transcriptional Elongation Factors