trichostatin-a and Huntington-Disease

Recent evidence suggests that the transcriptional coactivator peroxisome proliferator activated receptor gamma coactivator 1alpha (PGC-1alpha) is involved in the pathology of Huntington's Disease (HD). While animals lacking PGC-1alpha express lower levels of genes involved in antioxidant defense and oxidative phosphorylation in the brain, little is known about other targets for PGC-1alpha in neuronal cells and whether there are ways to pharmacologically target PGC-1alpha in neurons. Here, PGC-1alpha overexpression in SH-SY5Y neuroblastoma cells upregulated expression of genes involved in mitochondrial function, glucose transport, fatty acid metabolism, and synaptic function. Overexpression also decreased vulnerability to hydrogen peroxide-induced cell death and caspase 3 activation. Treatment of cells with the histone deacetylase inhibitors (HDACi's) trichostatin A and valproic acid upregulated PGC-1alpha and glucose transporter 4 (GLUT4). These results suggest that PGC-1alpha regulates multiple pathways in neurons and that HDACi's may be good candidates to target PGC-1alpha and GLUT4 in HD and other neurological disorders.

Topics: Apoptosis; Biological Transport; Caspase 3; Cell Line, Tumor; Enzyme Inhibitors; Fatty Acids; Gene Expression Regulation; Glucose; Glucose Transporter Type 4; Heat-Shock Proteins; Histone Deacetylase Inhibitors; Histone Deacetylases; Humans; Huntington Disease; Hydrogen Peroxide; Hydroxamic Acids; Neuroblastoma; Neurons; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Transcription Factors; Valproic Acid

Although expansion of trinucleotide repeats accounts for over 30 human diseases, mechanisms of repeat instability remain poorly understood. We show that a Drosophila model for the CAG/polyglutamine (polyQ) disease spinocerebellar ataxia type 3 recapitulates key features of human CAG-repeat instability, including large repeat changes and strong expansion bias. Instability is dramatically enhanced by transcription and modulated by nuclear excision repair and a regulator of DNA repair adenosine 3',5'-monophosphate (cAMP) response element-binding protein (CREB)-binding protein-a histone acetyltransferase (HAT) whose decreased activity contributes to polyQ disease. Pharmacological treatment to normalize acetylation suppressed instability. Thus, toxic consequences of pathogenic polyQ protein may include enhancing repeat instability.

Topics: Alleles; Animals; Animals, Genetically Modified; Anticipation, Genetic; CREB-Binding Protein; DNA Repair; Drosophila melanogaster; Drosophila Proteins; Female; Fragile X Syndrome; Genomic Instability; Histone Deacetylase Inhibitors; Humans; Huntington Disease; Hydroxamic Acids; Machado-Joseph Disease; Male; Models, Animal; Peptides; Transcription, Genetic; Transgenes; Trinucleotide Repeat Expansion; Trinucleotide Repeats

A defect in microtubule (MT)-based transport contributes to the neuronal toxicity observed in Huntington's disease (HD). Histone deacetylase (HDAC) inhibitors show neuroprotective effects in this devastating neurodegenerative disorder. We report here that HDAC inhibitors, including trichostatin A (TSA), increase vesicular transport of brain-derived neurotrophic factor (BDNF) by inhibiting HDAC6, thereby increasing acetylation at lysine 40 of alpha-tubulin. MT acetylation in vitro and in cells causes the recruitment of the molecular motors dynein and kinesin-1 to MTs. In neurons, acetylation at lysine 40 of alpha-tubulin increases the flux of vesicles and the subsequent release of BDNF. We show that tubulin acetylation is reduced in HD brains and that TSA compensates for the transport- and release-defect phenotypes that are observed in disease. Our findings reveal that HDAC6 inhibition and acetylation at lysine 40 of alpha-tubulin may be therapeutic targets of interest in disorders such as HD in which intracellular transport is altered.

Topics: Acetylation; Animals; Biological Transport, Active; Brain-Derived Neurotrophic Factor; Cell Line; Cells, Cultured; Cerebral Cortex; Histone Deacetylase 6; Histone Deacetylase Inhibitors; Histone Deacetylases; Huntington Disease; Hydroxamic Acids; Mice; Microscopy, Video; Microtubules; Molecular Motor Proteins; Neuroprotective Agents; Transport Vesicles; Tubulin; Visual Cortex; Vorinostat

Expansion of a polyglutamine tract in the huntingtin protein causes neuronal degeneration and death in Huntington's disease patients, but the molecular mechanisms underlying polyglutamine-mediated cell death remain unclear. Previous studies suggest that expanded polyglutamine tracts alter transcription by sequestering glutamine rich transcriptional regulatory proteins, thereby perturbing their function. We tested this hypothesis in Caenorhabditis elegans neurons expressing a human huntingtin fragment with an expanded polyglutamine tract (Htn-Q150). Loss of function alleles and RNA interference (RNAi) were used to examine contributions of C. elegans cAMP response element-binding protein (CREB), CREB binding protein (CBP), and histone deacetylases (HDACs) to polyglutamine-induced neurodegeneration. Deletion of CREB (crh-1) or loss of one copy of CBP (cbp-1) enhanced polyglutamine toxicity in C. elegans neurons. Loss of function alleles and RNAi were then used to systematically reduce function of each C. elegans HDAC. Generally, knockdown of individual C. elegans HDACs enhanced Htn-Q150 toxicity, but knockdown of C. elegans hda-3 suppressed toxicity. Neuronal expression of hda-3 restored Htn-Q150 toxicity and suggested that C. elegans HDAC3 (HDA-3) acts within neurons to promote degeneration in response to Htn-Q150. Genetic epistasis experiments suggested that HDA-3 and CRH-1 (C. elegans CREB homolog) directly oppose each other in regulating transcription of genes involved in polyglutamine toxicity. hda-3 loss of function failed to suppress increased neurodegeneration in hda-1/+;Htn-Q150 animals, indicating that HDA-1 and HDA-3 have different targets with opposing effects on polyglutamine toxicity. Our results suggest that polyglutamine expansions perturb transcription of CREB/CBP targets and that specific targeting of HDACs will be useful in reducing associated neurodegeneration.

Topics: Aging; Animals; Animals, Genetically Modified; Caenorhabditis elegans; Carbocyanines; CREB-Binding Protein; Cyclic AMP Response Element-Binding Protein; Disease Models, Animal; Enzyme Inhibitors; Gene Expression; Histone Deacetylases; Humans; Huntingtin Protein; Huntington Disease; Hydroxamic Acids; Nerve Degeneration; Nerve Tissue Proteins; Neurons; Nuclear Proteins; Peptides; Reverse Transcriptase Polymerase Chain Reaction; RNA Interference; RNA, Messenger