trichostatin-a and Nerve-Degeneration

Peripheral nerves, which consist of an axon and a unique glial cell called a Schwann cell, transduce signals from the brain and spinal cord to target organs. Peripheral nerve degeneration leads to distal motor or sensory disorders such as diabetic neuropathy, Charcot-Marie-Tooth disease, and Gullain-Barré syndrome, with symptoms such as dysesthesia, speech impairment, vision change, erectile dysfunction, and urinary incontinence. Schwann cells play an important role in peripheral nerve degeneration. Therefore, revealing the characteristics of Schwann cells will be essential in understanding peripheral neurodegeneration-related diseases for which there is currently no effective treatment. Trichostatin A (TSA) is a noncompetitive, reversible inhibitor of class I and II histone deacetylases (HDACs). HDACs have been shown not only to deacetylate histones but also to target non-histone proteins involved in diverse signaling pathways. Recent studies have revealed that diverse HDAC subtypes regulate peripheral neurodegeneration. Thus, regulating HDAC levels could be an effective strategy for the development of drugs targeting peripheral nerve-related diseases. In fact, the use of TSA has been investigated for the treatment of many diseases, including degenerative diseases of the central nervous system; however, the effects of TSA on peripheral neurodegeneration have not yet been well established. In this study, we revealed the effect of TSA on the process of peripheral neurodegeneration. TSA successfully inhibited myelin fragmentation, axonal degradation, and trans-dedifferentiation and proliferation of Schwann cells, which are essential phenotypes in peripheral neurodegeneration. Therefore, TSA could be a potential drug for patients suffering from peripheral neurodegeneration-related diseases.

Topics: Axons; Cell Dedifferentiation; Cell Proliferation; Cells, Cultured; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Myelin Sheath; Nerve Degeneration; Peripheral Nervous System Diseases; Schwann Cells

Axonal regeneration and related functional recovery following axonal injury in the adult central nervous system are extremely limited, due to a lack of neuronal intrinsic competence and the presence of extrinsic inhibitory signals. As opposed to what occurs during nervous system development, a weak proregenerative gene expression programme contributes to the limited intrinsic capacity of adult injured central nervous system axons to regenerate. Here we show, in an optic nerve crush model of axonal injury, that adenoviral (cytomegalovirus promoter) overexpression of the acetyltransferase p300, which is regulated during retinal ganglion cell maturation and repressed in the adult, can promote axonal regeneration of the optic nerve beyond 0.5 mm. p300 acetylates histone H3 and the proregenerative transcription factors p53 and CCAAT-enhancer binding proteins in retinal ganglia cells. In addition, it directly occupies and acetylates the promoters of the growth-associated protein-43, coronin 1 b and Sprr1a and drives the gene expression programme of several regeneration-associated genes. On the contrary, overall increase in cellular acetylation using the histone deacetylase inhibitor trichostatin A, enhances retinal ganglion cell survival but not axonal regeneration after optic nerve crush. Therefore, p300 targets both the epigenome and transcription to unlock a post-injury silent gene expression programme that would support axonal regeneration.

Topics: Age Factors; Animals; Animals, Newborn; Carrier Proteins; Cells, Cultured; Chromatin Immunoprecipitation; Disease Models, Animal; GAP-43 Protein; Gene Expression Regulation, Developmental; Green Fluorescent Proteins; Histone Deacetylase Inhibitors; Hydroxamic Acids; In Vitro Techniques; Nerve Crush; Nerve Degeneration; Nerve Regeneration; Nerve Tissue Proteins; Neurites; Optic Nerve Injuries; p300-CBP Transcription Factors; Rats; Retina; Retinal Ganglion Cells; Transfection; Tubulin; Tumor Suppressor Protein p53

Histone deacetylase (HDAC) inhibitors have been shown associated with neurodegenerative diseases. However, their effects on survival of dopaminergic neurons remain uncertain. In the present study, the HDAC inhibitor trichostatin A (TSA) was tested in following dopaminergic neuronal cell lines: rat N27, mouse MN9D, and human SH-SY5Y cells. Results demonstrated that a single TSA treatment resulted in decreased cell survival and increased apoptosis in dopaminergic neuronal cells. Pre-treatment with TSA resulted in exacerbated neurotoxic damage to dopaminergic neurons induced by 1-methyl-4-phenylpyridinium and rotenone. These results suggest that HDAC inhibitors may influence Parkinson's disease pathogenesis by inhibiting survival and increasing vulnerability of dopaminergic neurons to neurotoxins. Our data also suggested the importance of prudent use of HDAC inhibitors in therapy.

Topics: 1-Methyl-4-phenylpyridinium; Animals; Antiparkinson Agents; Apoptosis; Cell Line; Cell Survival; Dopamine; Drug Evaluation, Preclinical; Genetic Predisposition to Disease; Histone Deacetylase Inhibitors; Histone Deacetylases; Humans; Hydroxamic Acids; Mice; Nerve Degeneration; Neurons; Parkinson Disease; Rats; Rotenone; Substantia Nigra

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