tyrosine 3 monooxygenase

..In this review, we examine the structural basis for 14-3-3-ligand interactions, proposed functions of 14-3-3 in various signaling pathways, and emerging views of mechanisms that regulate 14-3-3 actions...

..These results suggest that accumulation of wild-type alpha-synuclein may play a causal role in Parkinson's disease and related conditions...

....

..This model offers new opportunities for the study of pathogenetic mechanisms and exploration of new therapeutic targets of particular relevance to human PD...

..Thus, the TOR signalling pathway broadly controls nutrient metabolism by sequestering several transcription factors in the cytoplasm...

..Collectively, these results suggest that PKCdelta phosphorylates PP2Ac to enhance its activity and thereby reduces TH-ser40 phosphorylation and TH activity and ultimately dopamine synthesis...

..These data indicate that GDNF delivery using a lentiviral vector system can prevent nigrostriatal degeneration and induce regeneration in primate models of PD and might be a viable therapeutic strategy for PD patients...

..Together, these data demonstrate that mutated alpha-synuclein mediates a proinflammatory response in microglia and this activity may participate in PD pathogenesis...

..Detection of dopamine-modulated behavioral changes in moderately depleted MPTP mice will allow for more efficacious use of this model in PD research...

....

..This strategy for isolating an enriched population of DA neurons should be useful for cellular and molecular studies of these neurons and for clinical applications in the treatment of Parkinson's disease...

..Hierarchical phosphorylation depends on the state of the substrate providing a novel form of control of tyrosine hydroxylase activation...

..Moreover, since blockade of either receptor subtype protected from METH, the activity of both DA receptor subtypes is required for the induction of toxicity by METH in the striatum...

..Thus, paraquat exposure yields a model that emphasizes the susceptibility of dopaminergic neurons to oxidative damage...

..Moreover, the induced cells secreted dopamine in response to depolarization. These results demonstrate the great therapeutic potential of human MSCs in PD...

..Finally, we show that the 14-3-3 dimer binds tightly to single molecules containing tandem repeats of phosphoserine motifs, implicating bidentate association as a signaling mechanism with molecules such as Raf, BAD, and Cbl...

..Our results also suggest that reactants derived from METH-induced oxidation of released DA may serve as neuronal signals that lead to microglial activation early in the neurotoxic process associated with METH...

..This cellular approach might be a restorative therapy in Parkinson's disease...

..These results suggest that Leonardo plays a role in the regulation of synaptic vesicle dynamics, a function which may underlie synaptic modulation properties enabling learning...

..TAZ may link events at the plasma membrane and cytoskeleton to nuclear transcription in a manner that can be regulated by 14-3-3...

..In addition, these partially lesioned animals did not respond to acute treatment with L-DOPA. This primate partial lesions model may be useful for examining potential neuroprotective or neurorestorative agents for PD...

..Our data show that SVZ neuroblasts are heterogeneous and that Pax6 is required in a cell-autonomous manner for the production of cells in the dopaminergic lineage...

..Results from testing of amphetamine-induced rotational behaviour suggest, moreover, that dopamine neurons implanted into the substantia nigra are also capable of integrating into the host circuitry at the functional level...

..The redox mechanisms of oxygen radical formation by MPTP, tyrosine hydroxylase, monoamine oxidase and aldehyde dehydrogenase will be discussed. Possible clinical applications of these mechanisms will be briefly presented...

..We conclude that reliable physiological criteria for VTA DA neuron identification have yet to be determined, and that the criteria currently being used are unreliable...

..We therefore conclude that RET signaling has no influence on the survival of dopaminergic neurons in the MPTP model of Parkinson's disease but rather facilitates the regeneration of dopaminergic axon terminals...

..They are interpreted as the teleostean dopaminergic system ascending to the striatum, since previous work [16] established that no noradrenergic neurons exist in the forebrain of the adult zebrafish...

..Thus, accumulation of soluble alpha-synuclein protein complexes can render endogenous dopamine toxic, suggesting a potential mechanism for the selectivity of neuronal loss in PD...

..Two 14-3-3 isoforms were detected. The major one was mainly cytoplasmic and to a lesser extent membrane-associated, whereas the minor isoform was associated with the detergent-resistant lipid rafts...

..In summary, we show that B'beta recruits PP2A to modulate TH activity in a tissue- and cell compartment specific fashion...

..Thus, introduction of the 14-3-3 zeta binding domain of GP Ibalpha into target cells might provide a method for regulating integrin-induced pathways in a variety of pathological conditions...

....

....

..As the fission yeast 14-3-3 homologs rad24 and rad25 mediate similar checkpoint effects, these results document a molecular mechanism for G2/M control that is conserved throughout eukaryotic evolution and regulated in human cells by p53...

..The results of this study indicate that BDNF and CNTF, acting through independent pathways, modulate NE and ACh cotransmission to regulate the level of sympathetic excitation or inhibition of cardiac myocytes...

..This suggests that declines in DA-related function during adulthood and senescence may be explained by losses in DA per se as opposed to DAergic neuropil...

....

..Inhibition of 14-3-3 may represent a useful therapeutic target for treatment of cancer and other diseases involving inappropriate cell survival...

..Taken together, these results suggest that 14-3-3zeta proteins may play a dynamic role in the regulation of cellular actin structures through the maintenance of phosphocofilin levels...

..This identifies dopamine as one of the few known endogenous regulators of adult neurogenesis with implications for the potential use of endogenous neural precursors in cell replacement strategies for Parkinson's disease...

..These results indicate that serine-216 phosphorylation and 14-3-3 binding negatively regulate Cdc25C and identify Cdc25C as a potential target of checkpoint control in human cells...

..These findings indicate that 14-3-3 proteins act as negative regulators of Cdc25 in controlling the G2-M transition...

..Promotion of these striatal TH-ir neurones may be beneficial in Parkinson's disease, particularly in the early stages when dopamine denervation is incomplete...

..The conservation of the hydrophobic residues Val-176, Leu-216, Leu-220, and Leu-227 among known 14-3-3 family members implies their general importance in ligand binding...

..We suggest that the differential striosome-matrix pattern of dopamine loss could be a key to identifying the mechanisms underlying the genesis of dystonia in DRD...

..These data demonstrate conservation of many genetic changes in murine and human neuroblastoma and suggest that further delineation of genetic abnormalities in murine tumors may identify genes important in human disease...

..These observations suggest that the generation of neural precursor cells is impaired in Parkinson disease as a consequence of dopaminergic denervation...

..This supports a paradigm in which the effects of phosphorylation on serine as well as tyrosine residues are mediated by inducible protein-protein interactions...

..Thus, Otp is one of the few known transcription factors that can determine aspects of the dopaminergic phenotype and the first known factor to control the development of the diencephalospinal dopaminergic system...

..Taken together, these results suggest that one function of C-TAK1 may be to regulate the interactions between Cdc25C and 14-3-3 in vivo by phosphorylating Cdc25C on serine 216...

..Thus, phosphovimentin, by sequestering 14-3-3 and limiting its availability to other target proteins can affect intracellular signaling processes that require 14-3-3...

..p27(Kip1) phosphorylated at Thr(198) exists only in the cytoplasm. Therefore, Akt promotes cell-cycle progression through the mechanisms of phosphorylation-dependent 14-3-3 binding to p27(Kip1) and cytoplasmic localization...

..These double-labeled cells of the posterior tubercle presumably represent the teleostean dopaminergic system ascending to the striatum...

....

..Thus, high expression of mutant human alpha-synuclein resulted in a progressive motor and widespread CNS gliotic phenotype independent of dopaminergic dysfunction in the Tg5093 line...

..This improved system efficiently corrects the rat model of PD...

..Together the data reveal a functional interaction between alpha-synuclein and PP2A that leads to PP2A activation and underscores a key role for alpha-synuclein in protein phosphorylation...

..Regulation of the cellular localization of HDAC4 and HDAC5 by 14-3-3 represents a mechanism for controlling the transcriptional activity of these class II HDAC proteins...

..They also suggest that extracellular Ca(2+) entry through such channels regulates cellular responses differently to Ca(2+) entry through voltage-operated Ca(2+) channels...

..Structural homology between the 14-3-3 NES structure and those within I kappa B alpha and p53 reveals a conserved topology recognized by the Crm1 nuclear export machinery...

..The present study supports the hypothesis that alpha-synuclein functions as a molecular chaperone protein that regulates the phosphorylation state of TH in a substrate and activity-dependent manner...

....

..The results are consistent with the hypothesis that a primary iron insufficiency produces a dopaminergic abnormality characterized as an overly activated dopaminergic system as part of the RLS pathology...

..Such TH-positive PCNs disappear after sympathectomy. These results suggest that the PCNs are made up of autonomic nerve fibers...

..This study implicates a role for developmental neurotoxicant exposure in the induction of neurodegenerative disorders such as PD...

..Our results suggest that the major aminergic systems described in adults are in place shortly after hatching, at a time when zebrafish are accessible to a battery of techniques to test neuronal function during behavior...

..Recruitment of the NAc as a target of METH neurotoxicity by alterations in DA homeostasis is significant in light of the important roles played by this brain structure...

..These results indicate that 14-3-3 proteins negatively regulate HDAC4 by preventing its nuclear localization and thereby uncover a novel regulatory mechanism for HDACs...

..These findings indicate that GFRalpha2/Ret signaling is required for normal cholinergic innervation of heart...

..This is consistent with studies in other mammals, indicating a role of stress-activated protein kinases in TH regulation...

....

..These data provide the first evidence that MDMA causes persistent loss of dopaminergic cell bodies in the SN...

..This suggests possible new therapeutic targets for Parkinson Disease...

..They also provide a molecular mechanism accounting for the ability of dopamine D(2) autoreceptors to inhibit dopamine synthesis and release from nigrostriatal nerve terminals...

..These findings suggest that peripheral systemic injection of TH AS ODN may be effective as hypotensive therapy in SHR...

..Nevertheless, these fibers did not originate from the SCG, contrary to TH-IR fibers...

..These findings further support a role for 14-3-3 proteins in the regulation of catecholamine biosynthesis and demonstrate isoform specificity for both TH and 14-3-3 proteins...

..14-3-3 may affect the localization of a protein by interfering with the function of a nearby targeting sequence, such as a nuclear localization sequence (NLS) or a nuclear export sequence (NES), on the binding partner...

..Reduced expression of the orphan nuclear receptor Nurr1 was also noted, suggesting that the co-ordinate regulation of dopamine synthesis is regulated through this transcription factor...

..The data also show that the cellular concentration of factors such as 14-3-3, CaMK I, and other yet unknown molecules may determine the subcellular localization of an individual HDAC member in a cell type and HDAC-specific manner...

..The activity and binding profile of alpha-synuclein suggests that it might act as a protein chaperone and that accumulation of alpha-synuclein could contribute to cell death in neurodegenerative diseases...

..Our results suggest that VEGF is a highly potent neurorescue molecule for Parkinson's disease therapy...

..The results suggest that long-term survival and functional integration into the DA-denervated striatum can be achieved with grafts of expanded mesencephalic precursors...

..Thus, in a model culture system where dopaminergic neurons innervate appropriate targets, excitotoxicity appears to be essential for the manifestation of the toxic actions of 6-hydroxydopamine, 1-methyl-4-phenylpyridinium and rotenone...

..We suggest that continuous and safe delivery of GDNF to the brain could be a potential way to optimize neural transplantation as a therapy for Parkinson's disease...

..Hence, prior cortical removal in 6OHDA-lesioned rats neuroprotected vSNc--but not VTA or dSNc--dopaminergic cells from death...

....

..Thus, these results suggest that the extent of nigrostriatal dopaminergic neuronal loss with 6-OHDA seems to be influenced by anaesthetic used during the surgery...

....

..These data have the potential to identify optimal transplantation parameters that can be applied to procedures utilizing stem cells, neural progenitors, and primary mesencephalic cells...

..The results of the present study show that treadmill exercise may provide therapeutic value for the treatment of Parkinson's disease patients...

..The fact that lesion of a single dopaminergic neuron can reduce dopamine transmission in more than one structure is probably important in generating the manifestations of Parkinson's disease...

..Hypoactivity of both the basal ganglia-thalamic and cerebellar-thalamic pathways might therefore be implicated in the development of parkinsonian symptoms...

..In summary, our results indicate that a loss of the midbrain dopaminergic cells induces a major change in parvalbumin expression within the zona incerta. This change may have key functional and clinical implications...

..Additionally, these results provide a foundation for future studies to assess toxic challenges of the developing nigrostriatal DA system, in vitro...

..In conclusion, the rotational movement and stepping test were not sensitive enough to distinguish severity of the striatal lesions, and learning acuity, but not retention of memories, was disturbed by the striatal lesions...

..Supplementation of U83836E and U74389G or other methylaminochromans and lazaroids in HB may be important for cold storage of donor neuronal cells...

..Angiotensin may play a pivotal role, via AT(1) receptors, in increasing the oxidative damage of dopaminergic cells, and treatment with AT(1) antagonists may reduce the progression of Parkinson's disease...

..In this model, subthalamotomy does not modify the firing pattern while levodopa treatment efficiently restores normal firing of SNpc neurons and does not appear to be toxic to them...

....

..Increases in brain levels of BH4 will test the hypothesis that the TPH cofactor can modulate the in vivo inactivation of TPH caused by MDMA as it does in vitro with NO/ROS. ..

..These studies will test novel hypotheses relating to the identification of reactive species that mediate METH and MDMA effects on monoamine nerve endings. ..

....

..Microarray-based scanning of the human genome has the potential to establish those genes or gene clusters that define the addictive phenotype, leading the way to proteomic-based studies of the bases of addiction. ..

....

..abstract_text> ..

..A better understanding of the mechanisms by which METH causes persistent damage to the DA neuronal system could lead to more targeted therapies and would open newer lines of investigation into this and other neurotoxic drugs of abuse. ..

..Research in this proposal is especially relevant to AIDS- related neuropathology, Parkinson's disease, and other neurodegenerative conditions in which microglial activation contributes to CNS damage. ..

..Research in this proposal is especially relevant to AIDS- related neuropathology, Parkinson's disease, and other neurodegenerative conditions in which microglial activation contributes to CNS damage. ..

..This will provide a unique and innovative approach to modeling the development and organization of the stress circuitry in mammals. ..

..Research in this proposal is especially relevant to AIDS- related neuropathology, Parkinson's disease, and other neurodegenerative conditions in which microglial activation contributes to CNS damage. ..

..Kuhn will remain extensively engaged in scientific mentoring activities. ..

..abstract_text> ..

..These findings will contribute to the development of new strategies to prevent the harmful maladaptive changes in catecholamine neurotransmission, while enhancing its beneficial adaptive aspects ..

....

....

....

..The effects of haloperidol on Ser19, Ser3l, and Ser4O phosphorylation will be studied by immunohistochemical and blot immunolabeling procedures using site- and phosphorylation state-specific antibodies. ..

..The results will elucidate potential mechanisms and sites where ovarian steroids, by affecting HF opioid systems, may influence hippocampal-dependent learning relevant to drug abuse. ..

..abstract_text> ..

..Cannabinoids may also influence the way pain signaling is processed by the locus coeruleus, revealing a potential new target for pain therapeutics. ..

..These studies will provide novel and relevant Information as to the contribution of VMAT2-containing vesicles in neuroprotection as well as in neurodegeneration under conditions of a metabolic stress. ..

....

..abstract_text> ..

..The research will likely identify the EPI/alpha-1 system as a new and important target for antidepressant and antistress medications ..

..abstract_text> ..

..abstract_text> ..