Post-transcriptional Regulation of Tyrosine Hydroxylase Expression in Adrenal Medulla and Brain

Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, New York 14642, USA.
Annals of the New York Academy of Sciences (Impact Factor: 4.38). 01/2009; 1148(1):238-48. DOI: 10.1196/annals.1410.054
Source: PubMed


It is well established that long-term stress leads to induction of tyrosine hydroxylase (TH) mRNA and TH protein in adrenal medulla and brain. This induction is usually associated with stimulation of the TH gene transcription rate. However, a number of studies have reported major discrepancies between the stress-induced changes in TH gene transcription, TH mRNA, and TH protein. These discrepancies suggest that post-transcriptional mechanisms also play an important role in regulating TH expression in response to stress and other stimuli. In this report, we summarize some of our findings and literature reports that demonstrate these discrepancies in adrenal medulla, locus ceruleus, and midbrain dopamine neurons. We then describe our recent work investigating the molecular mechanisms that mediate this post-transcriptional regulation in adrenal medulla and midbrain. Our results suggest that trans-acting factors binding to the polypyrimidine-rich region of the 3' untranslated region of TH mRNA play a role in these post-transcriptional mechanisms. A hypothetical cellular model describing this post-transcriptional regulation is proposed.

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    • "The single human TH gene undergoes alternative mRNA splicing generating four main isoforms (hTH1–hTH4), with variations in the length of the N-terminal, where hTH4 corresponds to the longest, fulllength isoform and hTH1 to the shortest and most abundant one, equivalent to rodent TH (Nagatsu, 1995). TH activity is tightly controlled by regulatory mechanisms at the transcriptional, translational and post-translational levels (Kumer and Vrana, 1996; Tank et al., 2008). The latter includes phosphorylation at several Ser/Thr residues at the N-terminal tail (Daubner et al., 2011). "
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    ABSTRACT: Tyrosine hydroxylase catalyses the hydroxylation of L-tyrosine to l-DOPA, the rate-limiting step in the synthesis of catecholamines. Mutations in the TH gene encoding tyrosine hydroxylase are associated with the autosomal recessive disorder tyrosine hydroxylase deficiency, which manifests phenotypes varying from infantile parkinsonism and DOPA-responsive dystonia, also termed type A, to complex encephalopathy with perinatal onset, termed type B. We generated homozygous Th knock-in mice with the mutation Th-p.R203H, equivalent to the most recurrent human mutation associated with type B tyrosine hydroxylase deficiency (TH-p.R233H), often unresponsive to l-DOPA treatment. The Th knock-in mice showed normal survival and food intake, but hypotension, hypokinesia, reduced motor coordination, wide-based gate and catalepsy. This phenotype was associated with a gradual loss of central catecholamines and the serious manifestations of motor impairment presented diurnal fluctuation but did not improve with standard l-DOPA treatment. The mutant tyrosine hydroxylase enzyme was unstable and exhibited deficient stabilization by catecholamines, leading to decline of brain tyrosine hydroxylase-immunoreactivity in the Th knock-in mice. In fact the substantia nigra presented an almost normal level of mutant tyrosine hydroxylase protein but distinct absence of the enzyme was observed in the striatum, indicating a mutation-associated mislocalization of tyrosine hydroxylase in the nigrostriatal pathway. This hypomorphic mouse model thus provides understanding on pathomechanisms in type B tyrosine hydroxylase deficiency and a platform for the evaluation of novel therapeutics for movement disorders with loss of dopaminergic input to the striatum. © The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email:
    Brain 08/2015; DOI:10.1093/brain/awv224 · 9.20 Impact Factor
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    • "A second possible explanation is that these genes are not regulated at a transcriptional level. There are many studies showing discrepancies between gene and protein expression which can be attributed to differences in gene regulatory mechanisms [23–26]. Posttranscriptional processes can be affected by mRNA stability and changes in translational efficiency. "
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    ABSTRACT: The use of an appropriate control group in human research is essential in investigating the level of a pathological disorder. This study aimed to compare three alternative sources of control lung tissue and to determine their suitability for gene and protein expression studies. Gene and protein expression levels of the vascular endothelial growth factor (VEGF) and gelatinase families and their receptors were measured using real-time reverse transcription polymerase chain reaction (RT-PCR) and immunohistochemistry. The gene expression levels of VEGFA, placental growth factor (PGF), and their receptors, fms-related tyrosine kinase 1 (FLT1), and kinase insert domain receptor (KDR) as well as matrix metalloproteinase-2 (MMP-2) and the inhibitors, tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) and TIMP-2 were significantly higher in lung cancer resections. The gene expression level of MMP-9 was significantly lower in the corresponding samples. Altered protein expression was also detected, depending on the area assessed. The results of this study show that none of the three control groups studied are completely suitable for gene and protein studies associated with the VEGF and gelatinase families, highlighting the need for researchers to be selective in which controls they opt for.
    The Scientific World Journal 04/2012; 2012:523840. DOI:10.1100/2012/523840 · 1.73 Impact Factor
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    • "These studies also showed that posttranscriptional regulations have a crucial role in the synthesis of TH in the SN/VTA (Chen et al., 2008; Tank et al., 2008). Posttranscriptional modulation occurs after the production of mRNA is completed, and includes the stabilization of the mRNA, the attachment to polyribosomes, and the regulation of the efficacy of translation into protein (Tank et al., 2008; Lenartowski and Goc, 2011). For all these reasons, we believe that is necessary to study TH protein levels in the SN/VTA in schizophrenia, to assess the possibility of pathologies that could be located in posttranscriptional steps in the synthesis of TH, rather than at the transcription level. "
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    ABSTRACT: Despite the importance of dopamine neurotransmission in schizophrenia, very few studies have addressed anomalies in the mesencephalic dopaminergic neurons of the substantia nigra/ventral tegmental area (SN/VTA). Tyrosine hydroxylase (TH) is the rate-limiting enzyme for the production of dopamine, and a possible contributor to the anomalies in the dopaminergic neurotransmission observed in schizophrenia. In this study, we had three objectives: 1) Compare TH expression (mRNA and protein) in the SN/VTA of schizophrenia and control postmortem samples. 2) Assess the effect of antipsychotic medications on the expression of TH in the SN/VTA. 3) Examine possible regional differences in TH expression anomalies within the SN/VTA. To achieve these objectives three independent studies were conducted: 1) A pilot study to compare TH mRNA and TH protein levels in the SN/VTA of postmortem samples from schizophrenia and controls. 2) A chronic treatment study was performed in rodents to assess the effect of antipsychotic medications in TH protein levels in the SN/VTA. 3) A second postmortem study was performed to assess TH and phosphorylated TH protein levels in two types of samples: schizophrenia and control samples containing the entire rostro-caudal extent of the SN/VTA, and schizophrenia and control samples containing only mid-caudal regions of the SN/VTA. Our studies showed impairment in the dopaminergic system in schizophrenia that could be mainly (or exclusively) located in the rostral region of the SN/VTA. Our studies also showed that TH protein levels were significantly abnormal in schizophrenia, while mRNA expression levels were not affected, indicating that TH pathology in this region may occur posttranscriptionally. Lastly, our antipsychotic animal treatment study showed that TH protein levels were not significantly affected by antipsychotic treatment, indicating that these anomalies are an intrinsic pathology rather than a treatment effect.
    Frontiers in Psychiatry 04/2012; 3:31. DOI:10.3389/fpsyt.2012.00031
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