Histone deacetylases as a therapeutic target in Huntington’s disease

• Type: National Conference Proceedings Book
• Date: 2008

Authors

Jorge M.A. Oliveira (Author) FFUP; Gonçalves J (Author) Other

Publisher

Revista Portuguesa de Farmácia

Conference National

1st National Meeting on Medicinal Chemistry

Porto, Portugal, 13 a 15 Novembro 2008

Scientific classification

FOS: Medical and Health sciences > Health sciences

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

Other information

Resumo (PT): Histone deacetylases (HDACs) are enzymes that act in concert with histone acetyltransferases (HATs) to regulate the levels of histone acetylation, and thereby modulate gene transcription. Increased histone acetylation by HATs relaxes chromatin, facilitating the association of the transcription machinery and thus enhancing gene transcription. Conversely, removal of acetyl groups by HDACs condenses chromatin leading to transcriptional repression [1]. Because transcriptional dysregulation, primarily related to decreases in gene expression is involved in Huntington’s disease (HD) pathogenesis, the strategy of inhibiting HDACs is hypothesized to be therapeutically useful in HD and other polyglutamine disorders [2]. Meaningfully, HDAC inhibitors have shown efficacy in mouse models of HD, improving survival, motor performance, and striatal atrophy [3]. However, the precise cellular changes evoked by HDAC inhibitors which are responsible for beneficial effects remain mostly unknown. Since HD neurodegeneration selectively targets striatal neurons, and the pathogenic mechanisms involve mitochondrial dysfunction [4], we tested whether treatment with HDAC inhibitors was able to improve mitochondrial function in HD striatal neurons [5]. Immortalized striatal precursor cells (STHdh) as well as primary cultures of striatal neurons, both derived from transgenic HD mice expressing full length mutant huntingtin (the HD causative gene) or their wild-type littermates, were used in functional imaging assays at single cell resolution, with dynamic monitoring of changes in intracellular calcium homeostasis and mitochondrial membrane potential. We evidenced that these HD striatal cellular models exhibit deficits in mitochondrial-dependent calcium handling. Also, we showed that treatment with two structurally unrelated HDAC inhibitors (sodium butyrate and trichostatin A) ameliorated mitochondrial deficits, leading to a faster restoration of normal calcium homeostasis following excitotoxic stimuli. Interestingly, striatal neurons challenged with excitotoxic stimuli responded with different patterns evidencing populations with increasing degrees of susceptibility. Notably, HDAC inhibitors improved calcium handling in the moderate but not in the most severely affected population, suggesting that treatment may be more beneficial in early-stage HD. In conclusion, inhibition of HDACs improves mitochondrial-dependent calcium handling in HD striatal neurons, suggesting that they have potential not only to prevent neuronal death but also to restore physiological neuronal function. Also, this effect may prove useful as a screening tool, and should be taken in consideration in the process of developing isoform selective HDAC inhibitors. References [1] Eberharter A. and Becker P.B., EMBO Reports, 2002, 3(3), 224-229. [2] Butler R. and Bates G.P., Nature Reviews Neuroscience, 2006, 7(10), 784-96. [3] Beal M.F. and Ferrante R.J., Nature Reviews Neuroscience, 2004, 5(5), 373-84. [4] Oliveira JMA et al., Journal of Neurochemistry, 2007, 101(1), 241-249. [5] Oliveira JMA et al., The Journal of Neuroscience, 2006, 26(43), 11174-11186. Acknowledgments The authors are grateful to the HighQ Foundation (USA), and Fundação para a Ciência e a Tecnologia, (Portugal) for financial support.

Abstract (EN): Histone deacetylases (HDACs) are enzymes that act in concert with histone acetyltransferases (HATs) to regulate the levels of histone acetylation, and thereby modulate gene transcription. Increased histone acetylation by HATs relaxes chromatin, facilitating the association of the transcription machinery and thus enhancing gene transcription. Conversely, removal of acetyl groups by HDACs condenses chromatin leading to transcriptional repression [1]. Because transcriptional dysregulation, primarily related to decreases in gene expression is involved in Huntington’s disease (HD) pathogenesis, the strategy of inhibiting HDACs is hypothesized to be therapeutically useful in HD and other polyglutamine disorders [2]. Meaningfully, HDAC inhibitors have shown efficacy in mouse models of HD, improving survival, motor performance, and striatal atrophy [3]. However, the precise cellular changes evoked by HDAC inhibitors which are responsible for beneficial effects remain mostly unknown. Since HD neurodegeneration selectively targets striatal neurons, and the pathogenic mechanisms involve mitochondrial dysfunction [4], we tested whether treatment with HDAC inhibitors was able to improve mitochondrial function in HD striatal neurons [5]. Immortalized striatal precursor cells (STHdh) as well as primary cultures of striatal neurons, both derived from transgenic HD mice expressing full length mutant huntingtin (the HD causative gene) or their wild-type littermates, were used in functional imaging assays at single cell resolution, with dynamic monitoring of changes in intracellular calcium homeostasis and mitochondrial membrane potential. We evidenced that these HD striatal cellular models exhibit deficits in mitochondrial-dependent calcium handling. Also, we showed that treatment with two structurally unrelated HDAC inhibitors (sodium butyrate and trichostatin A) ameliorated mitochondrial deficits, leading to a faster restoration of normal calcium homeostasis following excitotoxic stimuli. Interestingly, striatal neurons challenged with excitotoxic stimuli responded with different patterns evidencing populations with increasing degrees of susceptibility. Notably, HDAC inhibitors improved calcium handling in the moderate but not in the most severely affected population, suggesting that treatment may be more beneficial in early-stage HD. In conclusion, inhibition of HDACs improves mitochondrial-dependent calcium handling in HD striatal neurons, suggesting that they have potential not only to prevent neuronal death but also to restore physiological neuronal function. Also, this effect may prove useful as a screening tool, and should be taken in consideration in the process of developing isoform selective HDAC inhibitors. References [1] Eberharter A. and Becker P.B., EMBO Reports, 2002, 3(3), 224-229. [2] Butler R. and Bates G.P., Nature Reviews Neuroscience, 2006, 7(10), 784-96. [3] Beal M.F. and Ferrante R.J., Nature Reviews Neuroscience, 2004, 5(5), 373-84. [4] Oliveira JMA et al., Journal of Neurochemistry, 2007, 101(1), 241-249. [5] Oliveira JMA et al., The Journal of Neuroscience, 2006, 26(43), 11174-11186. Acknowledgments The authors are grateful to the HighQ Foundation (USA), and Fundação para a Ciência e a Tecnologia, (Portugal) for financial support.

Language: Portuguese

Type (Professor's evaluation): Scientific