Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.1.4.1 (phosphodiesterase)
 18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This review considers the 2 sources of neurotrophic factors in the peripheral nervous system (PNS), the neurons and the nonneuronal cells in the denervated distal nerve stumps, and their role in axon regeneration. Morphological assessment of regenerative success in response to administration of exogenous growth factors after nerve injury and repair has indicated a role of the endogenous neurotrophic factors from Schwann cells in the distal nerve stump. However, the increased number of axons may reflect more neurons regenerating their axons and/or increased numbers of axon sprouts from the same number of neurons. Using fluorescent dyes to count neurons that regenerated their axons across a suture site and into distal nerve stumps, brain-derived neurotrophic factor (BDNF) and glial cell-derived neurotrophic factor (GDNF) were found not to increase the number of neurons that regenerated their axons after immediate nerve repair. Nevertheless, the factors did reverse the deleterious effect of delayed nerve repair, indicating that the axons that regenerate into the distal nerve stump normally have access to sufficient levels of endogenous neurotrophic factors to sustain their regeneration, while neurons that do not have access to these factors require exogenous factors to sustain axon regeneration. Neurons upregulate neurotrophic factors after axotomy. The upregulation is normally slow, beginning after 7 days and occurring in association with a protracted period of axonal regeneration in which axons grow out from the proximal nerve stump across a suture site over a period of 1 month in rodents. This staggered axon regeneration across the suture site is accelerated by a 1-hour period of low-frequency electrical stimulation that simultaneously accelerates the expression of BDNF and its trkB receptor in the neurons. Elevation of the level of BDNF after 2 days to > 3 times that found in unstimulated neurons was accompanied by elevation of the level of cAMP and followed by accelerated upregulation of growth-associated genes, tubulin, actin, and GAP-43 and downregulation of neurofilament protein. Elevation of cAMP levels via rolipram inhibition of phosphodiesterase 4 mimicked the effect of the low-frequency electrical stimulation. In conclusion, the enhanced upregulation of neurotrophic factors in the electrically stimulated axotomized neurons accelerates axon outgrowth into the distal nerve stumps where endogenous sources of growth factors in the Schwann cells support the regeneration of the axons toward the denervated targets. The findings provide strong support for endogenous neurotrophic factors of axotomized neurons and of denervated Schwann cells playing a critical role in supporting axon regeneration in the PNS.
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PMID:The role of neurotrophic factors in nerve regeneration. 1922 5

Although tyrosyl-DNA phosphodiesterase (TDP1) is capable of removing blocked 3' termini from DNA double-strand break ends, it is uncertain whether this activity plays a role in double-strand break repair. To address this question, affinity-tagged TDP1 was overexpressed in human cells and purified, and its interactions with end joining proteins were assessed. Ku and DNA-PKcs inhibited TDP1-mediated processing of 3'-phosphoglycolate double-strand break termini, and in the absence of ATP, ends sequestered by Ku plus DNA-PKcs were completely refractory to TDP1. Addition of ATP restored TDP1-mediated end processing, presumably due to DNA-PK-catalyzed phosphorylation. Mutations in the 2609-2647 Ser/Thr phosphorylation cluster of DNA-PKcs only modestly affected such processing, suggesting that phosphorylation at other sites was important for rendering DNA ends accessible to TDP1. In human nuclear extracts, about 30% of PG termini were removed within a few hours despite very high concentrations of Ku and DNA-PKcs. Most such removal was blocked by the DNA-PK inhibitor KU-57788, but approximately 5% of PG termini were removed in the first few minutes of incubation even in extracts preincubated with inhibitor. The results suggest that despite an apparent lack of specific recruitment of TDP1 by DNA-PK, TDP1 can gain access to and can process blocked 3' termini of double-strand breaks before ends are fully sequestered by DNA-PK, as well as at a later stage after DNA-PK autophosphorylation. Following cell treatment with calicheamicin, which specifically induces double-strand breaks with protruding 3'-PG termini, TDP1-mutant SCAN1 (spinocerebellar ataxia with axonal neuropathy) cells exhibited a much higher incidence of dicentric chromosomes, as well as higher incidence of chromosome breaks and micronuclei, than normal cells. This chromosomal hypersensitivity, as well as a small but reproducible enhancement of calicheamicin cytotoxicity following siRNA-mediated TDP1 knockdown, suggests a role for TDP1 in repair of 3'-PG double-strand breaks in vivo.
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PMID:Tyrosyl-DNA phosphodiesterase and the repair of 3'-phosphoglycolate-terminated DNA double-strand breaks. 1950 54

Nogo-A, a neurite outgrowth inhibitor, is expressed exclusively on oligodendrocytes and neurons in the CNS. The central domain of Amino-Nogo spanning amino acids 567-748 in the human Nogo-A designated NIG, mediates persistent inhibition of axonal outgrowth and induces growth cone collapse by signaling through an as yet unidentified NIG receptor. We identified 82 NIG-interacting proteins by screening a high-density human protein microarray composed of 5000 proteins with a recombinant NIG protein as a probe. Following an intensive database search, we selected 12 neuron/oligodendrocyte-associated NIG interactors. Among them, we verified the molecular interaction of NIG with 2', 3'-cyclic nucleotide 3'-phosphodiesterase (CNP), a cell type-specific marker of oligodendrocytes, by immunoprecipitation and cell imaging analysis. Although CNP located chiefly in the cytoplasm of oligodendrocytes might not serve as a cell-surface NIG receptor, it could act as a conformational stabilizer for the intrinsically unstructured large segment of Amino-Nogo.
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PMID:Protein microarray analysis identifies cyclic nucleotide phosphodiesterase as an interactor of Nogo-A. 1950 46

The mammalian olfactory sense employs several olfactory subsystems situated at characteristic locations in the nasal cavity to detect and report on different classes of odors. These olfactory subsystems use different neuronal signal transduction pathways, receptor expression repertoires, and axonal projection targets. The Grueneberg ganglion (GG) is a newly appreciated olfactory subsystem with receptor neurons located just inside of the nostrils that project axons to a unique domain of interconnected glomeruli in the caudal olfactory bulb. It is not well understood how the GG relates to other olfactory subsystems in contributing to the olfactory sense. Furthermore, the range of chemoreceptors and the signal transduction cascade utilized by the GG have remained mysterious. To resolve these unknowns, we explored the molecular relationship between the GG and the GC-D neurons, another olfactory subsystem that innervates similarly interconnected glomeruli in the same bulbar region. We found that mouse GG neurons express the cGMP-associated signaling proteins phosphodiesterase 2a, cGMP-dependent kinase II, and cyclic nucleotide gated channel subunit A3 coupled to a chemoreceptor repertoire of cilia-localized particulate guanylyl cyclases (pGC-G and pGC-A). The primary cGMP signaling pathway of the GG is shared with the GC-D neurons, unifying their target glomeruli as a unique center of olfactory cGMP signal transduction. However, the distinct chemoreceptor repertoire in the GG suggests that the GG is an independent olfactory subsystem. This subsystem is well suited to detect a unique set of odors and to mediate behaviors that remained intact in previous olfactory perturbations.
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PMID:Grueneberg ganglion olfactory subsystem employs a cGMP signaling pathway. 1956 23

Programmed cell death is a term which refers to a genetic decision of self-killing or suicide of a cell. Programmed cell death is not restricted to multicellular organisms and was described in a wide range of unicellular eukaryotes, indicating phylogenetically conserved functions, that participate in an adaptive response to cellular stress. Here we review and discuss our observations recently published in the EMBO Journal,(1) that non-dividing fission yeast, Schizosaccharomyces pombe, exhibits a DNA damage response leading to cell death. We found that Tdp1 protects quiescent S. pombe cells against oxidative DNA damage. Tdp1 is a well-conserved tyrosyl-DNA phosphodiesterase required for single-strand break DNA repair, the mutation of Tdp1 is responsible for the recessively inherited syndrome spinocerebellar ataxia with axonal neuropathy (SCAN1) in humans. We found that tdp1 mutant yeast cells grow, as well as the wild-type cells, during the vegetative state, but progressively die in the quiescent state. We showed that, in the absence of Tdp1, the accumulation of unrepaired oxidative DNA damage triggers a genetic response, leading to checkpoint-dependent (ATM/ATR) nuclear DNA degradation, reminiscent of apoptosis. Our results indicate that the reactive oxygen species (ROS) produced during mitochondrial respiration are the main DNA damaging agents in the physiological quiescent state.
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PMID:Unrepaired oxidative DNA damage induces an ATR/ATM apoptotic-like response in quiescent fission yeast. 1957 71

Traumatic human spinal cord injury (SCI) causes devastating and long-term hardships. These are due to the irreparable primary mechanical injury and secondary injury cascade. In particular, oligodendrocyte cell death, white matter axon damage, spared axon demyelination, and the ensuing dysfunction in action potential conduction lead to the initial deficits and impair functional recovery. For these reasons, and that oligodendrocyte and axon survival may be related, various neuroprotective strategies after spinal cord injury are being investigated. We previously demonstrated that oligodendrocytes in the adult rat epicenter ventrolateral funiculus (VLF) express 3'-5'-cyclic adenosine monophosphate-dependent phosphodiesterase 4 (PDE4) subtypes and that their death was attenuated up to 3 days after contusive cervical SCI when rolipram, a specific inhibitor of PDE4, was administered. Here, we report that (1) there are more oligodendrocyte somata in the adult rat epicenter VLF, (2) descending and ascending axonal conductivity in the VLF improves, and that (3) there are fewer hindlimb footfall errors during grid-walking at 5 weeks after contusive cervical SCI when rolipram is delivered for 2 weeks. This is the first demonstration of improved descending and ascending long-tract axonal conductivity across a SCI with this pharmacological approach. Since descending long-tract axonal conductivity did not return to normal, further evaluations of the pharmacokinetics and therapeutic window of rolipram as well as optimal combinations are necessary before consideration for neuroprotection in humans with SCI.
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PMID:Effects of rolipram on adult rat oligodendrocytes and functional recovery after contusive cervical spinal cord injury. 1963 28

Tyrosyl DNA phosphodiesterase (TDP1) is a DNA 3'-end processing enzyme that preferentially hydrolyses the bond between the 3'-end of DNA and stalled DNA topoisomerase 1. the importance of TDP1 is highlighted by its association with the human genetic disease spinocerebellar ataxia with axonal neuropathy. TDP1 comprises of a highly conserved C-terminus phosphodiesterase domain and a less conserved N-terminus tail. the importance of the N-terminus domain was suggested by its interaction with Lig3alpha. Here we show that this interaction is promoted by serine 81 that is located within a putative S/TQ site in the N-terminus domain of TDP1. Although mutation of serine 81 to alanine had no impact on TDP1 activity in vitro and had little impact on the ability of TDP1 to mediate the rapid repair of CPT- or IR-induced DNA breaks in vivo, it led to marked reduction of protein stability. Moreover, it reduced the ability of TDP1 to promote cell survival following genotoxic stress. Together, our findings highlight a novel mechanism for regulating TDP1 function in mammalian cells that is not directly related to its enzymatic activity.
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PMID:TDP1 serine 81 promotes interaction with DNA ligase IIIalpha and facilitates cell survival following DNA damage. 2000 12

Oligodendrocytes are the myelin-forming cells of the central nervous system that facilitate transmission of axonal electrical impulses. Using transgenic mice expressing 2',3' cyclic nucleotide 3' phosphodiesterase (CNPase)-enhanced green fluorescent protein, a three-dimensional reconstruction tool and analysis, we illustrate that three morphologically different oligodendrocyte types exist in the hippocampus. Those of the ramified type have the most numerous processes, the largest cell body, occupy the largest area and form beaded-like structures, due to mitochondria aggregates, along the processes. Stellar-shaped oligodendrocytes have smaller cell bodies and their processes cover a significantly smaller area. Those of the smooth subtype have a small cell body with at most two processes. In addition to these types, a large number of oligodendrocytes were found that faintly express CNPase-enhanced green fluorescent protein. More than 50% of the faint type colocalized with NG2 and 91% with oligodendrocyte transcription factor-2, whereas 94% of NG2-immunoreactive and 45% of oligodendrocyte transcription factor-2-immunoreactive cells were faintly CNPase-enhanced green fluorescent protein positive. Based on the complexity of the overall structure, the three types probably represent stages of a maturation process such that one subtype can morph into another. Thus, the least complex 'smooth' cell would represent the youngest oligodendrocyte that matures into the stellar type and eventually progresses to become the most complex ramified oligodendrocyte. Investigation of the distribution pattern revealed that the highest density of oligodendrocytes was found in the stratum lacunosum-moleculare and the hilar region. The distribution analysis of oligodendrocyte subclasses revealed a tendency for different cell types to segregate in large non-overlapping areas. This observation suggests that morphologically, and possible functionally, different oligodendrocytes are topographically segregated.
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PMID:Subclasses of oligodendrocytes populate the mouse hippocampus. 2010 32

Neuronal plasticity deficits underlie many of the neurobehavioral problems seen in fetal alcohol spectrum disorders (FASD). Recently, we showed that third trimester alcohol exposure leads to a persistent disruption in ocular dominance (OD) plasticity. For instance, a few days of monocular deprivation results in a robust reduction of cortical regions responsive to the deprived eye in normal animals, but not in ferrets exposed early to alcohol. This plasticity deficit can be reversed if alcohol-exposed animals are treated with a phosphodiesterase type 1 (PDE1) inhibitor during the period of monocular deprivation. PDE1 inhibition can increase cAMP and cGMP levels, activating transcription factors such as the cAMP response element binding protein (CREB) and the serum response factor (SRF). SRF is important for many plasticity processes such as LTP, LTD, spine motility, and axonal pathfinding. Here we attempt to rescue OD plasticity in alcohol-treated ferrets using a Sindbis viral vector to express a constitutively active form of SRF during the period of monocular deprivation. Using optical imaging of intrinsic signals and single-unit recordings, we observed that overexpression of a constitutively active form of SRF, but neither its dominant-negative nor GFP, restored OD plasticity in alcohol-treated animals. Surprisingly, this restoration was observed throughout the extent of the primary visual cortex and most cells infected by the virus were positive for GFAP rather than NeuN. This finding suggests that overexpression of SRF in astrocytes may reduce the deficits in neuronal plasticity seen in models of FASD.
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PMID:Overexpression of serum response factor restores ocular dominance plasticity in a model of fetal alcohol spectrum disorders. 2016 36

The present study assessed the ability of a combined immunomodulatory treatment using (1) selective depletion of peripheral macrophages with liposomal-encapsulated clodronate, and (2) rolipram, a type 4 phosphodiesterase (PDE4) inhibitor, to promote neuroprotection and improve locomotor recovery following experimental contusion SCI. We demonstrate that delivery of either liposomal clodronate or rolipram alone promotes neuroprotection, enhances myelinated tissue sparing, and improves hindlimb functional recovery. Combined treatment with liposomal clodronate and rolipram produced the greatest improvement in locomotor recovery (inter-limb coordination, paw placement, and toe clearance), at 4 weeks post-injury (2.9 points). Retrograde tracing revealed substantial axonal sparing and/or sprouting from several brainstem motor nuclei, and hindlimb motor cortex. The combined treatment with these two drugs promoted the greatest amount of axonal sparing (3- to 4-fold increase compared to controls). Histological assessments revealed that combined treatment with clodronate/ rolipram resulted in a significant reduction in lesion volume (51%) and lesion area at the injury epicenter (45%), and significantly increased the extent of myelinated tissue sparing. Immunohistochemical studies showed a qualitative reduction in the accumulation of ED-1(+) macrophages within the injured spinal cord 5 weeks after injury. Our results demonstrate robust neuroprotection and improved hindlimb locomotor function using a combined immunomodulatory treatment strategy consisting of liposomal clodronate and rolipram. The present data suggest that clinical trials with acute delivery of combination immunomodulatory therapies may be warranted. This article is part of a Special Issue entitled "Interaction between repair, disease, & inflammation."
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PMID:A combination immunomodulatory treatment promotes neuroprotection and locomotor recovery after contusion SCI. 2033 67


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