Steffan JS, Bodai L, Pallos J, Poelman M, McCampbell A, Apostol BL, Kazantsev A, Schmidt E, Zhu YZ, Greenwald M, Kurokawa R, Housman DE, Jackson GR, Marsh JL and Thompson LMHistone deacetylase inhibitors arrest polyglutamine-dependent neurodegeneration in Drosophila. Nature 413: 739-743

Department of Psychiatry and Human Behavior, Gillespie 2121, University of California, Irvine, California 92697, USA.
Nature (Impact Factor: 41.46). 11/2001; 413(6857):739-43. DOI: 10.1038/35099568
Source: PubMed


Proteins with expanded polyglutamine repeats cause Huntington's disease and other neurodegenerative diseases. Transcriptional dysregulation and loss of function of transcriptional co-activator proteins have been implicated in the pathogenesis of these diseases. Huntington's disease is caused by expansion of a repeated sequence of the amino acid glutamine in the abnormal protein huntingtin (Htt). Here we show that the polyglutamine-containing domain of Htt, Htt exon 1 protein (Httex1p), directly binds the acetyltransferase domains of two distinct proteins: CREB-binding protein (CBP) and p300/CBP-associated factor (P/CAF). In cell-free assays, Httex1p also inhibits the acetyltransferase activity of at least three enzymes: p300, P/CAF and CBP. Expression of Httex1p in cultured cells reduces the level of the acetylated histones H3 and H4, and this reduction can be reversed by administering inhibitors of histone deacetylase (HDAC). In vivo, HDAC inhibitors arrest ongoing progressive neuronal degeneration induced by polyglutamine repeat expansion, and they reduce lethality in two Drosophila models of polyglutamine disease. These findings raise the possibility that therapy with HDAC inhibitors may slow or prevent the progressive neurodegeneration seen in Huntington's disease and other polyglutamine-repeat diseases, even after the onset of symptoms.

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    • "As histones are hypoacetylated in HD, blocking HDAC4 translation by increasing miR-22 could promote neuronal survival. It is important to note that the use of HDAC inhibitors, such as SAHA, can ameliorate the symptoms of HD in animal models, making them promising therapeutics in HD (Ferrante et al., 2003; Hockly et al., 2003; Mielcarek et al., 2011; Steffan et al., 2001; Thomas et al., 2008). Other dysregulated miRNAs in HD are targeted by REST, a master regulator that largely represses neuronal genes in neuronal and non-neuronal cells. "
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    ABSTRACT: Neurological conditions, such as Alzheimer’s disease and stroke, represent a prevalent group of devastating illnesses with few treatments. Each of these diseases or conditions is in part characterized by the dysregulation of many genes, including those that code for microRNAs (miRNAs) and histone deacetylases (HDACs). Recently, a complex relationship has been uncovered linking miRNAs and HDACs and their ability to regulate one another. This provides a new avenue for potential therapeutics as the ability to reinstate a careful balance between miRNA and HDACs has lead to improved outcomes in a number of in vitro and in vivo models of neurological conditions. In this review, we will discuss recent findings on the interplay between miRNAs and HDACs and its implications for pathogenesis and treatment of neurological conditions, including amyotrophic lateral sclerosis, Alzheimer’s disease, Huntington’s disease and stroke.
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    • "From there it became instrumental for studying genetic mutations, and today researchers around the world use Drosophila as a model system for studying human diseases, including neurodegeneration. Many key discoveries that have helped in advancing the neurodegenerative disease field have been made using flies as a model system including, but not limited to, the identification of candidate genes as causes and therapies of disease (Fernandez-Funez et al., 2000; Steffan et al., 2001; Warrick et al., 1999), in vivo evidence for RNA-mediated neurodegeneration (Jin et al., 2003; Li et al., 2008), the identification of ER-golgi trafficking inhibition as a contributor to alpha-synuclein-associated toxicity in Parkinson's disease (Cooper et al., 2006) and the identification of a molecular link between the ubiquitin-proteasome system and autophagy (Pandey et al., 2007). Thomas Morgan, Alfred Sturtevant, Calvin Bridges and Hermann Muller were among the first pioneers of genetic research in Drosophila. "
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    • "Aberrant histone acetylation and/or impaired function of the histone acetylation machinery have been linked to pathogenic progression in numerous neurological conditions including neurodegeneration [2], [3], [4]. HDAC inhibitors have been used consistently and successfully in an array of neurological disease models including poly-glutamine toxicity, spinal muscular atrophy, intracerebral hemorrhage and cerebral ischemia [5], [6], [7], [8], [9], [10], [11]. CBP is a transcriptional co-activator with HAT activity that was shown to be important for long-term memory processes, which depend on de novo gene expression [12], [13], [14]. "
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    ABSTRACT: Epigenetic transcriptional regulation by histone acetylation depends on the balance between histone acetyltransferase (HAT) and deacetylase activities (HDAC). Inhibition of HDAC activity provides neuroprotection, indicating that the outcome of cerebral ischemia depends crucially on the acetylation status of histones. In the present study, we characterized the changes in histone acetylation levels in ischemia models of focal cerebral ischemia and identified cAMP-response element binding protein (CREB)-binding protein (CBP) as a crucial factor in the susceptibility of neurons to ischemic stress. Both neuron-specific RNA interference and neurons derived from CBP heterozygous knockout mice showed increased damage after oxygen-glucose deprivation (OGD) in vitro. Furthermore, we demonstrated that ischemic preconditioning by a short (5 min) subthreshold occlusion of the middle cerebral artery (MCA), followed 24 h afterwards by a 30 min occlusion of the MCA, increased histone acetylation levels in vivo. Ischemic preconditioning enhanced CBP recruitment and histone acetylation at the promoter of the neuroprotective gene gelsolin leading to increased gelsolin expression in neurons. Inhibition of CBP's HAT activity attenuated neuronal ischemic preconditioning. Taken together, our findings suggest that the levels of CBP and histone acetylation determine stroke outcome and are crucially associated with the induction of an ischemia-resistant state in neurons.
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