Calcium-induced toxicity in cellular models of Huntington´s disease: early homeostatic changes and protective effect of HDAC inhibitors

• 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 C (Author) Other; Hayden MR (Author) Other; Nicholls DG (Author) Other; Ellerby LM (Author) Other; Rego AC (Author) Other

Publisher

Society for Neuroscience

Washington

Conference International

35th Annual Meeting of the Society for Neuroscience

Washington, USA, 2005

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 progressive and fatal neurological disorder caused by a mutant form of huntingtin (htt). Evidence suggests that disturbed calcium homeostasis and transcriptional deregulation play an important role in the selective striatal neurodegeneration observed in HD. Immortalized striatal progenitor cells from knock-in mice and primary striatal neurons from YAC128 mice were used as HD models expressing full-length htt. Calcium-induced toxicity was induced by brief exposure to 4Br-A23187 or NMDA-receptor activation. Using real-time imaging we simultaneously measured changes in intracellular calcium, mitochondrial membrane potential (mmp) and somatic swelling. Recovery from excitotoxic stimuli was influenced by pharmacological manipulation of mmp, highly suggesting mitochondrial involvement, which was further emphasized by experiments performed in pyruvate-based media. In both HD models, cells expressing mutant htt presented a significantly delayed recovery from excitotoxic stimuli when compared to wild-type controls. This delayed recovery was associated with a slower restoration of intracellular calcium, mitochondrial depolarization and somatic swelling. Treatment with histone deacetylase (HDAC) inhibitors improved recovery from calcium-induced toxicity, highly suggesting enhanced functioning of intracellular mechanisms involved in calcium homeostasis. Population analysis of striatal neurons suggested the existence of subpopulations refractory to treatment with HDAC inhibitors. These results provide an in vitro explanation for neuroprotective effects of HDAC inhibitors observed in animal models of HD. Support Contributed By: Foundations: HighQ, Calouste Gulbenkian, FCT

Abstract (EN): Huntington's disease (HD) is a progressive and fatal neurological disorder caused by a mutant form of huntingtin (htt). Evidence suggests that disturbed calcium homeostasis and transcriptional deregulation play an important role in the selective striatal neurodegeneration observed in HD. Immortalized striatal progenitor cells from knock-in mice and primary striatal neurons from YAC128 mice were used as HD models expressing full-length htt. Calcium-induced toxicity was induced by brief exposure to 4Br-A23187 or NMDA-receptor activation. Using real-time imaging we simultaneously measured changes in intracellular calcium, mitochondrial membrane potential (mmp) and somatic swelling. Recovery from excitotoxic stimuli was influenced by pharmacological manipulation of mmp, highly suggesting mitochondrial involvement, which was further emphasized by experiments performed in pyruvate-based media. In both HD models, cells expressing mutant htt presented a significantly delayed recovery from excitotoxic stimuli when compared to wild-type controls. This delayed recovery was associated with a slower restoration of intracellular calcium, mitochondrial depolarization and somatic swelling. Treatment with histone deacetylase (HDAC) inhibitors improved recovery from calcium-induced toxicity, highly suggesting enhanced functioning of intracellular mechanisms involved in calcium homeostasis. Population analysis of striatal neurons suggested the existence of subpopulations refractory to treatment with HDAC inhibitors. These results provide an in vitro explanation for neuroprotective effects of HDAC inhibitors observed in animal models of HD. Support Contributed By: Foundations: HighQ, Calouste Gulbenkian, FCT

Language: Portuguese

Type (Professor's evaluation): Scientific