Histone acetylation and recovery from excitotoxicity in striatal cells expressing full-length mutant huntingtin

• Type: International Conference Proceedings Book
• Date: 2005

Authors

Jorge M.A. Oliveira (Author) FFUP; Chen S (Author) Other; Almeida S (Author) Other; Riley R (Author) Other; Gonçalves J (Author) Other; Oliveira CR (Author) Other; Hayden MR (Author) Other; Nicholls DG (Author) Other; Ellerby LM (Author) Other; Rego AC (Author) Other

Publisher

Journal of Neurology, Neurosurgery and Psychiatry

Conference International

HDA meeting: World Congress on Huntington's disease

Manchester, UK, 2005

Indexing

ISI Web of Science

Scientific classification

FOS: Medical and Health sciences > Health sciences

CORDIS: Health sciences > Neuroscience > Neurochemistry ; Health sciences > Neuroscience > Neurophysiology ; Health sciences > Pharmacological sciences

Other information

Resumo (PT): Huntington’s disease (HD) is a dominant neurodegenerative disorder that selectively targets striatal neurons. HD is caused by a CAG expansion in the gene encoding huntingtin (htt). Disturbed calcium homeostasis and transcriptional deregulation are believed to play an important role in HD pathology. Histone deacetylase (HDAC) inhibitors increase transcription and were shown to be neuroprotective in animal models of HD. However, the cellular changes that are responsive for neuroprotection remain to be fully understood. In the present study we established two HD cellular models of calcium-induced toxicity and tested the hypothesis that the neuroprotective effects of HDAC inhibitors can be explained by an improved neuronal ability to recover from excitotoxic stimuli. Striatal cells from HdhQ111 mice and primary striatal neurons from YAC128 mice were challenged with 4Br-A23187 or NMDA, respectively, to evaluate changes in calcium homeostasis, mitochondrial membrane potential (MMP) and somatic swelling. Reestablishment of basal intracellular calcium following excitotoxic stimuli was influenced by mitochondrial inhibition with oligomycin or rotenone. Mutant htt expression was associated with a slower restoration of intracellular calcium, MMP and somatic swelling. These parameters were ameliorated by protracted treatment with HDAC inhibitors. These results suggest improvement in calcium homeostasis mechanisms, strengthening the use of HDAC inhibitors in HD treatment. Acknowledgements: HighQ Foundation; Calouste Gulbenkian Foundation; Fundação para a Ciência e a Tecnologia

Abstract (EN): Huntington’s disease (HD) is a dominant neurodegenerative disorder that selectively targets striatal neurons. HD is caused by a CAG expansion in the gene encoding huntingtin (htt). Disturbed calcium homeostasis and transcriptional deregulation are believed to play an important role in HD pathology. Histone deacetylase (HDAC) inhibitors increase transcription and were shown to be neuroprotective in animal models of HD. However, the cellular changes that are responsive for neuroprotection remain to be fully understood. In the present study we established two HD cellular models of calcium-induced toxicity and tested the hypothesis that the neuroprotective effects of HDAC inhibitors can be explained by an improved neuronal ability to recover from excitotoxic stimuli. Striatal cells from HdhQ111 mice and primary striatal neurons from YAC128 mice were challenged with 4Br-A23187 or NMDA, respectively, to evaluate changes in calcium homeostasis, mitochondrial membrane potential (MMP) and somatic swelling. Reestablishment of basal intracellular calcium following excitotoxic stimuli was influenced by mitochondrial inhibition with oligomycin or rotenone. Mutant htt expression was associated with a slower restoration of intracellular calcium, MMP and somatic swelling. These parameters were ameliorated by protracted treatment with HDAC inhibitors. These results suggest improvement in calcium homeostasis mechanisms, strengthening the use of HDAC inhibitors in HD treatment. Acknowledgements: HighQ Foundation; Calouste Gulbenkian Foundation; Fundação para a Ciência e a Tecnologia

Language: Portuguese

Type (Professor's evaluation): Scientific