CA150 expression delays striatal cell death in overexpression and knock-in conditions for mutant huntingtin neurotoxicity
| Autor: | Ashwani Kumar Thakur, Emmanuel Brouillet, Christian Neri, James Pearson, Patrick Aebischer, Margarita Arango, Sébastien Holbert, Etienne Régulier, Dania Zala, Nicole Déglon, Ronald Wetzel |
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| Přispěvatelé: | Institut National de la Santé et de la Recherche Médicale (INSERM), Ecole Polytechnique Fédérale de Lausanne (EPFL), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Department of Molecular Genetics and Microbiology, Duke University Medical Center, University of Tennessee, Région Ile-de-France, Fondation pour la Recherche Médicale, INSERM Avenir, Swiss National Science Foundation (Switzerland), National Institute of Health Grants R01 AG19322 and R01 GM071037, Huntington's Disease Society of America, ProdInra, Migration |
| Jazyk: | angličtina |
| Rok vydání: | 2006 |
| Předmět: |
Huntingtin
striatum Mutant Apoptosis Huntington Disease/*metabolism/*pathology Rats Sprague-Dawley 0302 clinical medicine neuron death DISEASE PROTEIN Nuclear protein Transcription Factors/*metabolism Cells Cultured transcription factor Neurons Neurons/*metabolism/*pathology TRANSGENIC MICE 0303 health sciences Huntingtin Protein [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology Cultured REPRESSES TRANSCRIPTION General Neuroscience Nuclear Proteins Articles MOUSE MODEL Huntington Disease neuroprotection [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] Transcriptional Elongation Factors Neuron death CREB-BINDING PROTEIN Programmed cell death Huntington huntingtin Cells Neurotoxins RNA-POLYMERASE-II Nerve Tissue Proteins KAPPA-B Biology Nerve Tissue Proteins/genetics/*metabolism Neuroprotection Neurotoxins/metabolism 03 medical and health sciences Nuclear Proteins/genetics/*metabolism medicine POLYGLUTAMINE EXPANSION Animals [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] Nuclear export signal INACTIVATING LENTIVIRAL VECTORS 030304 developmental biology Neurotoxicity AXONAL-TRANSPORT medicine.disease Molecular biology Corpus Striatum Rats nervous system Mutation Corpus Striatum/*metabolism/*pathology Sprague-Dawley 030217 neurology & neurosurgery [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology Transcription Factors |
| Zdroj: | Journal of Neuroscience Journal of Neuroscience, 2006, 26 (17), pp.4649-4659. ⟨10.1523/JNEUROSCI.5409-05.2006⟩ Journal of Neuroscience, Society for Neuroscience, 2006, 26 (17), pp.4649-4659. ⟨10.1523/JNEUROSCI.5409-05.2006⟩ |
| ISSN: | 0270-6474 1529-2401 |
| DOI: | 10.1523/JNEUROSCI.5409-05.2006⟩ |
| Popis: | 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)38repeat normally found in CA150. We excluded the possibility that rescue may be caused by the (Gln-Ala)38repeat interacting with polyGlns and, by doing so, blocking mutant htt toxicity. In contrast, we found the (Gln-Ala)38repeat is required for the nuclear restriction of exogenous CA150, suggesting that rescue requires nuclear CA150. Additionally, we found the (Gln-Ala)38repeat 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. |
| Databáze: | OpenAIRE |
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