Activation of Tyrosine Hydroxylase mRNA Translation by cAMP in Midbrain Dopaminergic Neurons

Department of Pharmacology and Physiology, Box 711, University of Rochester Medical Center, 601 Elmwood Ave., Rochester, NY 14642, USA.
Molecular pharmacology (Impact Factor: 4.13). 07/2008; 73(6):1816-28. DOI: 10.1124/mol.107.043968
Source: PubMed


During prolonged stress or chronic treatment with neurotoxins, robust compensatory mechanisms occur that maintain sufficient levels of catecholamine neurotransmitters in terminal regions. One of these mechanisms is the up-regulation of tyrosine hydroxylase (TH), the enzyme that controls catecholamine biosynthesis. In neurons of the periphery and locus coeruleus, this up-regulation is associated with an initial induction of TH mRNA. In contrast, this induction either does not occur or it is nominal in mesencephalic dopamine neurons. The reasons for this lack of compensatory TH mRNA induction remain obscure, because so little is known about the regulation of TH expression in these neurons. In this study, we test whether activation of the cAMP signaling pathway regulates TH gene expression in two rodent models of midbrain dopamine neurons, ventral midbrain organotypic slice cultures and MN9D cells. Our results demonstrate that elevation of cAMP leads to induction of TH protein and TH activity in both model systems; however, TH mRNA levels are not up-regulated by cAMP. The induction of TH protein is the result of a novel post-transcriptional mechanism that activates TH mRNA translation. This translational activation is mediated by sequences within the 3' untranslated region (UTR) of TH mRNA. Our results support a model in which cAMP induces or activates trans-factors that interact with the TH mRNA 3'UTR to increase TH protein synthesis. An understanding of this novel regulatory mechanism may help to explain the control of TH gene expression and consequently dopamine biosynthesis in midbrain neurons under different physiological and pathological conditions.

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    • "An increase in cAMP due to GLP-1R activation could possibly promote axonal sprouting and thus restore innervations to damaged brain regions (Filbin, 2003). Upregulation of PKA/cAMP pathway via GLP-1R stimulation could also lead to increased TH/TPH expression which could result in restoration of the DA, 5-HT, and NA neurotransmitter systems (Gueorguiev et al., 2006; Chen et al., 2008; Dunkley et al., 2004; Foguet et al., 1993; Yamamoto et al., 2003). Administration of EX-4 has promoted recovery in several animal models of disease including PD, Alzheimer's, stroke, ALS, and Huntington's disease (Bertilsson et al., 2008; Harkavyi et al., 2008; Li et al., 2012; Martin et al., 2009). "
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    ABSTRACT: Research on Parkinson's disease (PD) has mainly focused on the degeneration of the dopaminergic neurons of nigro-striatal pathway; however, post-mortem studies have demonstrated that other brain regions such as the locus coeruleus (LC) and raphe nuclei (RN) are significantly affected as well. Degeneration of these crucial neuronal cell bodies may be responsible for depressive behavior and cognitive decline present in the pre-motor stage of PD. We have thus set out to create a pre-motor rodent model of PD which mimics the early stages of the condition. N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4), a selective noradrenergic neurotoxin, and parachloroampetamine (pCA), a selective serotonergic neurotoxin, were utilized concomitantly with bilateral 6-hydroxydopamine (6-OHDA) injections into the striatum to produce a pre-motor rodent model of PD with partial deficits in the dopaminergic, noradrenergic, and serotonergic systems. Our model exhibited a depressive/anhedonic condition as assessed using sucrose preference testing and the forced swim test. Our model also demonstrated deficits in object memory. These behavioral impairments were accompanied by a decline in both tissue and extracellular levels of all three neurotransmitters in both the frontal cortex and striatum. Immunohistochemistry also revealed a decrease in TH+ cells in the LC and substantia nigra. Exendin-4 (EX-4), a glucagon-like peptide-1 receptor (GLP-1R) agonist, promoted recovery of both the biochemical and behavioral dysfunction exhibited by our model. EX-4 was able to preserve the functional integrity of the dopaminergic, noradrenergic, and serotonergic systems. In conclusion, we have generated a novel animal model of PD that recapitulates certain pre-motor symptomology. These symptoms and causative physiology are ameliorated upon treatment with EX-4 and thus it could be used as a possible therapy for the non-motor symptoms prominent in the early stages of PD.
    Preview · Article · Aug 2012 · Neuropeptides
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    • "In addition, recent studies on the synthesis of TH have shown that the regulation of the production of TH is very different in the SN/VTA than in other catecholaminergic neurons (Wong and Tank, 2007; Chen et al., 2008; Tank et al., 2008). 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). "
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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.
    Full-text · Article · Apr 2012 · Frontiers in Psychiatry
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    • " and ( ii ) activation of nicotinic acetylcho - line receptors and changes in neuronal activity and intracel - lular Ca 2+ as sole mediators of nicotine - induced TH mRNA in SNc . Elevations in cAMP powerfully induce TH gene transcription in many cells , but had no effects on the level of TH mRNA in rodent midbrain slices or a midbrain cell line ( Chen et al . 2008 ) . There were increases in TH protein , however these were shown to be through a novel post - transcriptional mechanism . In a subsequent study , Radcliffe et al . ( 2009 ) reported that the increased TH mRNA observed in rat midbrain DA neurons following nicotine was not solely due to activation of nicotinic acetylcholine receptors ( S"
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    ABSTRACT: Degeneration of dopamine (DA) neurons in the substantia nigra pars compacta (SNc) causes the motor symptoms of Parkinson's disease. The development of cell-replacement therapies for Parkinson's disease motor symptoms is hampered by poor acquisition and retention of the DA phenotype by endogenous and transplanted neurons. Factors which regulate the DA phenotype in the adult SNc are, therefore, keenly sought. Transcription of the rate-limiting enzyme in DA synthesis, tyrosine hydroxylase, and possibly other DA genes, is known to be regulated by changes in membrane potential and intracellular Ca²⁺. Furthermore, emerging evidence indicates DA gene transcription is sensitive to fast membrane potential changes and intracellular Ca²⁺ transients, that is, those associated with normal rates and patterns of neuronal activity. In other words, the DA phenotype is activity-dependent. In this review, we highlight the importance of spatiotemporal Ca²⁺ dynamics for regulating gene expression in cells, and the possible role of fast Ca²⁺ dynamics associated with normal rates and patterns of neuronal activity. We review evidence supporting activity- and Ca²⁺-dependent regulation of the DA phenotype in cells, including SNc neurons, as well as knowledge about the molecular pathways intervening between intracellular Ca²⁺ and TH gene expression. We describe the electrophysiology of SNc DA neurons, emphasizing features that may regulate DA gene expression. We conclude by bringing together this information in a model of how neuronal activity might regulate the DA phenotype in SNc neurons.
    Preview · Article · Feb 2012 · Journal of Neurochemistry
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