trichostatin-a and Neurodegenerative-Diseases

Histone deacetylase 6 (HDAC6) plays a key role in a variety of neurological disorders, which makes it attractive drug target for the treatment of Alzheimer's disease, Parkinson's disease, and memory/learning impairment. The selectivity of HDAC6 inhibitors (sHDAC6Is) are widely considered to be susceptible to the sizes of their Cap group and the physicochemical properties of their linker or zinc-binding group, which makes the discovery of new sHDAC6Is extremely difficult. With the discovery of the distinct selectivity between Trichostatin A (TSA) enantiomers, the chirality residing in the connective units between TSA's Cap and linker shows a great impact on its selectivity. However, the mechanism underlining ( S)-TSA's selectivity is still elusive, and the way chirality switches the selective ( S)-TSA to nonselective ( R)-TSA is unknown. In this study, multiple computational approaches were collectively applied to explore, validate, and differentiate the binding modes of two TSA enantiomers in HDACs (especially the HDAC6) at atomic level. First, two nonconservative residues (G200/M205 and Y197/F202 in HDAC1/6) in loop3 and four conservative residues deep inside the hydrophobic binding pocket were discovered as the decisive residues of ( S)-TSA's selectivity toward HDAC6. Then, a novel mechanism underlying the selectivity of ( S)-TSA toward HDAC6 was proposed, which was composed of the trigger by two nonconservative residues F202 and M205 in HDAC6 and a subsequently improved fit of ( S)-TSA deep inside HDAC6's hydrophobic binding pocket. TSA enantiomers were used as a molecular probe to explore the mechanism underlying sHDAC6Is' selectivity in this study. Because of their decisive roles in ( S)-TSA's selectivity to HDAC6, both F202 and M205 in HDAC6 should be especially considered in the discovery of novel sHDAC6Is.

Topics: Histone Deacetylase 1; Histone Deacetylase 6; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Molecular Dynamics Simulation; Neurodegenerative Diseases; Protein Conformation

Class I histone deacetylase (HDAC) inhibitors are believed to have positive effects on neurite outgrowth, synaptic plasticity, and neurogenesis in adult brain. However, the downstream molecular targets of class I HDAC inhibitors in neurons are not clear. Although class I HDAC inhibitors are thought to broadly promote transcription of many neuronal genes through enhancement of histone acetylation, the affected gene set may include unidentified genes that are essential for neuronal survival and function. To identify novel genes that are targets of class I HDAC inhibitors, we used a microarray to screen transcripts from neuronal cultures and evaluated changes in protein and mRNA expression following treatment with four HDAC inhibitors. We identified tescalcin (Tesc) as the most strongly up-regulated gene following treatment with class I HDAC inhibitors in neurons. Moreover, hippocampal neurons overexpressing TESC showed a greater than 5-fold increase in the total length of neurites and number of branch points compared with controls. These findings highlight a potentially important role for TESC in mediating the neuroprotective effect of class I HDAC inhibitors. TESC may also be involved in the development of brain and neurodegenerative diseases through epigenetic mechanisms.

Topics: Animals; Calcineurin; Calcium; Calcium-Binding Proteins; Cluster Analysis; Epigenesis, Genetic; Gene Expression Profiling; Green Fluorescent Proteins; Hippocampus; Histone Deacetylase 1; Histone Deacetylase Inhibitors; Hydroxamic Acids; Male; Mice; Mice, Inbred C57BL; Neurites; Neurodegenerative Diseases; Neurogenesis; Neurons; Neuroprotective Agents; Oligonucleotide Array Sequence Analysis; Plasmids; Real-Time Polymerase Chain Reaction; Software; Up-Regulation; Valproic Acid; Vorinostat

Ataxia telangiectasia is a neurodegenerative disease caused by mutation of the Atm gene. Here we report that ataxia telangiectasia mutated (ATM) deficiency causes nuclear accumulation of histone deacetylase 4 (HDAC4) in neurons and promotes neurodegeneration. Nuclear HDAC4 binds to chromatin, as well as to myocyte enhancer factor 2A (MEF2A) and cAMP-responsive element binding protein (CREB), leading to histone deacetylation and altered neuronal gene expression. Blocking either HDAC4 activity or its nuclear accumulation blunts these neurodegenerative changes and rescues several behavioral abnormalities of ATM-deficient mice. Full rescue of the neurodegeneration, however, also requires the presence of HDAC4 in the cytoplasm, suggesting that the ataxia telangiectasia phenotype results both from a loss of cytoplasmic HDAC4 as well as its nuclear accumulation. To remain cytoplasmic, HDAC4 must be phosphorylated. The activity of the HDAC4 phosphatase, protein phosphatase 2A (PP2A), is downregulated by ATM-mediated phosphorylation. In ATM deficiency, enhanced PP2A activity leads to HDAC4 dephosphorylation and the nuclear accumulation of HDAC4. Our results define a crucial role of the cellular localization of HDAC4 in the events leading to ataxia telangiectasia neurodegeneration.

Topics: Active Transport, Cell Nucleus; Animals; Ataxia Telangiectasia; Ataxia Telangiectasia Mutated Proteins; Cell Cycle Proteins; Cell Nucleus; Cyclic AMP Response Element-Binding Protein; DNA-Binding Proteins; Female; Histone Deacetylases; Histones; Hydroxamic Acids; Male; MEF2 Transcription Factors; Mice; Myogenic Regulatory Factors; Neurodegenerative Diseases; Phosphorylation; Protein Phosphatase 2; Protein Serine-Threonine Kinases; Tumor Suppressor Proteins

Histone deacetylases (HDAC) are enzymes that maintain chromatin in a condensate state, related with absence of transcription. We have studied the role of HDAC on learning and memory processes. Both eyeblink classical conditioning (EBCC) and object recognition memory (ORM) induced an increase in histone H3 acetylation (Ac-H3). Systemic treatment with HDAC inhibitors improved cognitive processes in EBCC and in ORM tests. Immunohistochemistry and gene expression analyses indicated that administration of HDAC inhibitors decreased the stimulation threshold for Ac-H3, and gene expression to reach the levels required for learning and memory. Finally, we evaluated the effect of systemic administration of HDAC inhibitors to mice models of neurodegeneration and aging. HDAC inhibitors reversed learning and consolidation deficits in ORM in these models. These results point out HDAC inhibitors as candidate agents for the palliative treatment of learning and memory impairments in aging and in neurodegenerative disorders.

Topics: Acetylation; Aging; Analysis of Variance; Animals; Association Learning; Blinking; Conditioning, Classical; Disease Models, Animal; Enzyme Inhibitors; Histone Deacetylase Inhibitors; Histones; Hydroxamic Acids; Kainic Acid; Male; Memory; Mice; Mice, Mutant Strains; Neurodegenerative Diseases; Pattern Recognition, Visual; Time Factors