Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.14.16.2 (tyrosine hydroxylase)
 14,760 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This study demonstrated that dopaminergic MN9D and PC12 cells were more vulnerable than non-dopaminergic N2A cells to the challenge by proteasome inhibitor MG132, which could be alleviated by reductants and alpha-methyl tyrosine (alpha-MT), a specific tyrosine hydroxylase inhibitor. Furthermore, challenging non-dopaminergic N2A cells with exogenous DA could aggravate MG132-induced cell viability decrease, which could be abrogated by reductants but not by alpha-MT. It was observed that alpha-MT could decrease endogenous DA content in dopaminergic MN9D and PC12 cells while N2A cells could take in exogenous DA into cytosol. The endogenous DA in dopaminergic cells was demonstrated to inhibit proteasome activity in the cells and further sensitize the proteasome to MG132 inhibition. In addition, the endogenous DA was also implicated for the increased level of lipid peroxidation and ubiquitinated proteins as well as inclusion bodies formation when non-dopaminergic cells were challenged with exogenous DA. Taken together it is proposed that endogenous DA in dopaminergic neurons could promote selective dopaminergic neurodegeneration, especially under the conditions of exopathic or idiopathic defects of ubiquitin-proteasome system (UPS), which may be abolished by reductant remedy.
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PMID:Endogenous dopamine (DA) renders dopaminergic cells vulnerable to challenge of proteasome inhibitor MG132. 1848 77

The D2/D3 dopamine receptor agonist pramipexole, protects against toxin-induced dopaminergic neuronal destruction but its mechanism of action is unknown. Inflammation following glial cell activation contributes to cell death in Parkinson's disease and we now report on the effects of acute or chronic administration of pramipexole on lipopolysaccharide (LPS) induced inflammation and nigral dopaminergic cell death in the rat. At 48 h and 30 days following supranigral administration of LPS, approximately 70% of tyrosine hydroxylase (TH) immunoreactive (-ir) cells in substantia nigra had degenerated with a corresponding loss of TH-ir terminals in the striatum. In rats acutely treated with pramipexole (2x1 mg/kg; s.c.) 48 h following LPS application, there was no difference in the number of TH-ir cells or terminals compared to LPS-treated rats receiving vehicle. However, the continuous subcutaneous infusion of pramipexole for 7 days prior to LPS and 21 days subsequently, produced a marked preservation of both TH-ir cells and terminals. At 48 h or 30 days, LPS induced an up-regulation of ubiquitin-ir within the nigral TH-ir neurones, which was reduced by pramipexole treatment. Thirty days following supranigral LPS administration (9 days after the end of infusion), (+)-amphetamine (5 mg/kg, i.p.) caused robust ipsiversive rotation. In rats treated with LPS but receiving continuous subcutaneous administration of pramipexole, (+)-amphetamine-induced rotation was markedly reduced. LPS-induced increase in the levels of inflammatory markers, were not affected by either acute administration or continuous infusion of pramipexole. Continuous infusion of pramipexole protected dopaminergic neurones against inflammation induced degeneration but without modification of the inflammatory response.
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PMID:Continuous subcutaneous infusion of pramipexole protects against lipopolysaccharide-induced dopaminergic cell death without affecting the inflammatory response. 1857 49

Parkinson's disease (PD) has been proposed to result from a combination of genetic susceptibility and environmental exposure. Dysfunction of the ubiquitin-proteasome system (UPS) has been implicated in neuron degeneration and in pathogenesis of PD. Nurr1, a member of nuclear receptor superfamily, is a potential susceptibility gene for PD. In this in vitro and in vivo study, we investigated whether Nurr1 deficiency may predispose to environmental proteasome inhibitors-induced neuron injury. We found that lactacystin, an irreversible proteasome inhibitor, caused greater injury to SH-SY5Y cells that Nurr1 expression has been suppressed by small interference RNA (siRNA). On the contrary, the Nurr1 overexpressed SH-SY5Y cells by Nurr1 expression vector transfection rescued the lactacystin-induced injury. In vivo, stereotactic microinjection with lactacystin into right median forebrain bundle (MFB) of mice caused significant inhibition of the proteasome activity in both Nurr1 knock out heterozygous (Nurr1 +/-) mice and their littermate wild-type (Nurr1 +/+) mice. At same time, we found that there was a severer loss of tyrosine hydroxylase (TH)-positive neurons in substantia nigra (SN) and greater reduction of striatal dopamine (DA) levels in Nurr1 +/- mice as compared with that in Nurr1 +/+ mice. Furthermore, lactacystin-induced increase of cleaved PARP, cleaved caspase3 and p53 and decrease of bcl-2 in SN was significantly enhanced in Nurr1 +/- mice. These findings suggest that reduction in Nurr1 expression increases susceptibility to DAergic neuron injury induced by UPS impairment.
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PMID:Nurr1 deficiency predisposes to lactacystin-induced dopaminergic neuron injury in vitro and in vivo. 1857 22

Therapeutic vaccination against tumor antigens without induction of autoimmunity remains a major challenge in cancer immunotherapy. Here, we show for the first time effective therapeutic vaccination followed by suppression of established spontaneous neuroblastoma metastases using a tyrosine hydroxylase (TH) DNA minigene vaccine. We identified three novel mouse TH (mTH3) derived peptides with high predicted binding affinity to MHC class I antigen H2-K(k) according to the prediction program SYFPEITHI and computer modeling of epitopes into the MHC class I antigen binding groove. Subsequently, a DNA minigene vaccine was generated based on the expression vector pCMV-F3Ub encoding mutated ubiquitin (Gly(76) to Ala(76)) and mTH3. Prophylactic and therapeutic efficacies of this vaccine were established following oral delivery with attenuated Salmonella typhimurium SL7207. Only mice immunized with mTH3 were free of spontaneous liver metastases. This effect was clearly dependent on ubiquitin and high affinity of the mTH epitopes to MHC class I antigens. Specifically, we showed a crucial role for minigene expression as a stable ubiquitin-Ala(76) fusion peptide for vaccine efficacy. The immune response following the mTH3 DNA minigene vaccination was mediated by CD8(+) T cells as indicated by infiltration of primary tumors and TH-specific cytolytic activity in vitro. Importantly, no cell infiltration was detectable in TH-expressing adrenal medulla, indicating the absence of autoimmunity. In summary, we show effective therapeutic vaccination against neuroblastoma with a novel rationally designed TH minigene vaccine without induction of autoimmunity providing an important baseline for future clinical application of this strategy.
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PMID:A rationally designed tyrosine hydroxylase DNA vaccine induces specific antineuroblastoma immunity. 1864 33

The etiology of Parkinson disease (PD) is unclear but may involve environmental toxins such as pesticides leading to dysfunction of the ubiquitin proteasome system (UPS). Here, we measured the relative toxicity of ziram (a UPS inhibitor) and analogs to dopaminergic neurons and examined the mechanism of cell death. UPS (26 S) activity was measured in cell lines after exposure to ziram and related compounds. Dimethyl- and diethyldithiocarbamates including ziram were potent UPS inhibitors. Primary ventral mesencephalic cultures were exposed to ziram, and cell toxicity was assessed by staining for tyrosine hydroxylase (TH) and NeuN antigen. Ziram caused a preferential damage to TH+ neurons and elevated alpha-synuclein levels but did not increase aggregate formation. Mechanistically, ziram altered UPS function through interfering with the targeting of substrates by inhibiting ubiquitin E1 ligase. Sodium dimethyldithiocarbamate administered to mice for 2 weeks resulted in persistent motor deficits and a mild reduction in striatal TH staining but no nigral cell loss. These results demonstrate that ziram causes selective dopaminergic cell damage in vitro by inhibiting an important degradative pathway implicated in the etiology of PD. Chronic exposure to widely used dithiocarbamate fungicides may contribute to the development of PD, and elucidation of its mechanism would identify a new potential therapeutic target.
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PMID:Ziram causes dopaminergic cell damage by inhibiting E1 ligase of the proteasome. 1881 10

This report describes pathological changes within the grafted neurons of another patient with Parkinson's disease (PD) who died 14 years posttransplantation. Although numerous healthy appearing grafted neurons were present at this long-term time point, some displayed Lewy bodies as evidenced by alpha-synuclein, ubiquitin, and thioflavin-S staining. Additionally, there was a general loss of dopamine transporter-immunoreactivity in grafted neurons. Some grafted cell displayed a loss of tyrosine hydroxylase. These data support the emerging concept that PD-like pathology is seen in young grafted neurons when they survive long term.
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PMID:Transplanted dopaminergic neurons develop PD pathologic changes: a second case report. 1900 93

Hypothalamic norepinephrine (NE) release regulates arterial pressure by altering sympathetic nervous system activity. Because angiotensin (Ang) (1-7) decreases hypothalamic NE release and this effect may be correlated with a diminished NE synthesis, we hypothesize that Ang-(1-7) down-regulates tyrosine hydroxylase (TH), the rate-limiting enzyme in catecholamines biosynthesis. We investigated the effect of Ang-(1-7) on centrally TH activity and expression. TH activity was evaluated by the release of tritiated water from (3)H-l-tyrosine. TH expression and phosphorylation were determined by western blot. Hypothalami from normotensive or spontaneously hypertensive rats pre-incubated with Ang-(1-7) showed a significant decrease in TH specific activity. Ang-(1-7) caused a decrease in TH phosphorylation at Ser19 and Ser40 residues. The heptapeptide induced a decrease in TH expression that was blocked by an AT(2) receptor antagonist and not by an AT(1) or Mas receptor antagonist, suggesting the involvement of AT(2) receptors. The proteasome inhibitor MG132 blocked the Ang-(1-7)-mediated TH reduction. In addition, Ang-(1-7) increased the amount of TH-ubiquitin complexes, indicating that the Ang-(1-7)-mediated TH degradation involves ubiquitin conjugation prior to proteasome degradation. We conclude that Ang-(1-7) down-regulates TH activity and expression centrally leading to a decrease in the central NE system activity.
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PMID:Angiotensin-(1-7) through AT receptors mediates tyrosine hydroxylase degradation via the ubiquitin-proteasome pathway. 1918 50

The ubiquitin-proteasome system (UPS) and the autophagy-lysosomal pathway (ALP) are the two most important components of cellular mechanisms for protein degradation. In the present study we investigated the functional relationship of the two systems and the interactional role of p53 in vitro. Our study showed that the proteasome inhibitor lactacystin induced an increase in p53 level and autophagy activity, whereas inhibition of p53 by pifithrin-alpha or small interference RNA (siRNA) of p53 attenuated the autophagy induction and increased protein aggregation. Furthermore, we found that pretreatment with the autophagy inhibitor 3-methyladenine or beclin 1 siRNA further activated p53 and its downstream apoptotic pathways, while the autophagy inducer rapamycin showed the opposite effects. Moreover, we demonstrated that rapamycin pretreatment increased tyrosine hydroxylase (TH) protein level in dopamine (DA) neurons, which was associated with its induction of autophagy to degrade aggregated proteins. Our results suggest that p53 can mediate proteasomal inhibition-induced autophagy enhancement which in turn can partially block p53 or its downstream mitochondria-dependent apoptotic pathways. Further autophagy induction with rapamycin protects DA neurons from lactacystin-mediated cell death by downregulating p53 and its related apoptotic pathways and by inducing autophagy to degrade aggregated proteins. Therefore, rapamycin may be a promising drug for protection against neuronal injury relevant to Parkinson disease (PD). Our studies thus provide a mechanistic insight into the functional link between the two protein degradation systems.
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PMID:An insight into the mechanistic role of p53-mediated autophagy induction in response to proteasomal inhibition-induced neurotoxicity. 1933 30

Dysfunction of the proteasome has been suggested to contribute in the degeneration of nigrostriatal dopaminergic neurons. Here, we investigated to determine whether systematic administration of proteasome inhibitor, carbobenzoxy-L: -gamma-t-butyl-L: -glutamyl-L: -alanyl-L: -leucinal (PSI) protects against MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) neurotoxicity in mice. Three administrations of MPTP at 1-h intervals to mice reduced significantly the concentration of dopamine, DOPAC (3,4-dihydroxyphenylacetic acid) and HVA (homovanillic acid) in the striatum after 5 days. In contrast, PSI (0.3 and 1.0 mg/kg) prevented a significant decrease in dopamine, DOPAC and HVA contents of the striatum 5 days after MPTP treatment. In our Western blot analysis study, PSI at a dose of 1.0 mg/kg prevented a significant decrease in TH (tyrosine hydroxylase) protein and a significant increase in glial fibrillary acidic protein 5 days after MPTP treatment. Furthermore, our immunohistochemical study showed that PSI at a dose of 1.0 mg/kg prevented a significant loss in TH immunopositive neurons in the striatum and substantia nigra 5 days after MPTP treatment. In contrast, PSI caused a significant increase in the number of intense ubiquitin immunopositive cells in the striatum and substantia nigra 5 days after MPTP treatment. These results indicate that proteasome inhibitors can protect against MPTP neurotoxicity in mice. The neuroprotective effect of PSI against dopaminergic cell damage may be mediated by the elevation of ubiquitination. Thus, our findings provide further valuable information for the pathogenesis of Parkinson's disease.
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PMID:Systemic administration of proteasome inhibitor protects against MPTP neurotoxicity in mice. 1937 Apr 11

The systemic rotenone model of Parkinson's disease (PD) accurately replicates many aspects of the pathology of human PD and has provided insights into the pathogenesis of PD. The major limitation of the rotenone model has been its variability, both in terms of the percentage of animals that develop a clear-cut nigrostriatal lesion and the extent of that lesion. The goal here was to develop an improved and highly reproducible rotenone model of PD. In these studies, male Lewis rats in three age groups (3, 7 or 12-14 months) were administered rotenone (2.75 or 3.0 mg/kg/day) in a specialized vehicle by daily intraperitoneal injection. All rotenone-treated animals developed bradykinesia, postural instability, and/or rigidity, which were reversed by apomorphine, consistent with a lesion of the nigrostriatal dopamine system. Animals were sacrificed when the PD phenotype became debilitating. Rotenone treatment caused a 45% loss of tyrosine hydroxylase-positive substantia nigra neurons and a commensurate loss of striatal dopamine. Additionally, in rotenone-treated animals, alpha-synuclein and poly-ubiquitin positive aggregates were observed in dopamine neurons of the substantia nigra. In summary, this version of the rotenone model is highly reproducible and may provide an excellent tool to test new neuroprotective strategies.
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PMID:A highly reproducible rotenone model of Parkinson's disease. 1938 59


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