As nigrostriatal neurons degenerate, either during Parkinson's disease or after exposure to neurotoxins, compensatory mechanisms are activated in the surviving striatal nerve terminals to increase dopamine biosynthesis and release. In contrast, gene expression of tyrosine hydroxylase (TH), the enzyme that catalyzes the rate-limiting step in dopamine biosynthesis, is not apparently induced in midbrain cell bodies. This lack of compensatory induction of TH mRNA is surprising, since one would expect robust homeostatic mechanisms to up-regulate TH gene expression and consequently further enhance dopamine biosynthesis in spared nigrostriatal neurons. There is very little information concerning the receptors and intracellular signaling mechanisms that regulate TH gene expression in nigrostriatal neurons. Without this information, it is impossible to understand this lack of compensatory induction and it is difficult to design new therapies to up-regulate TH in surviving nigrostriatal neurons during Early Parkinson's disease or after exposed to neurotoxins. The studies in this proposal are aimed at filling in this gap in our knowledge. The hypotheses being tested in the proposal is that agonists which excite dopaminergic midbrain neurons lead to stimulation of TH gene transcription rate in the midbrain of healthy animals. However, this response may be inhibited in the surviving neurons of animals with lesions of the nigrostriatal pathway. Several aspects of this hypothesis will be tested under the following specific aims: (1) To test whether muscarinic and/or other stimulatory agonists activate whether muscarinic and/or other stimulatory agonists activate TH gene transcription rate and phosphorylate or induce pertinent transcription factors in midbrain cell bodies of healthy rats; (2) To test whether candidate transcription factors are essential for the response of the TH gene to muscarine; and (3) To test whether the TH gene responds to muscarinic (or other stimulatory agonists) in surviving midbrain cell bodies after partial lesions of the nigrostriatal pathway and whether TH gene expression can be induced pharmacologically in these surviving neurons. These studies will shed light on the molecular mechanisms regulating the TH gene in the midbrain and may lead to new therapeutic strategies for the treatment of Parkinson's disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS039415-01
Application #
6032223
Study Section
Special Emphasis Panel (ZRG1-BDCN-2 (01))
Program Officer
Edwards, Emmeline
Project Start
2000-01-15
Project End
2003-11-30
Budget Start
2000-01-15
Budget End
2000-11-30
Support Year
1
Fiscal Year
2000
Total Cost
$232,198
Indirect Cost
Name
University of Rochester
Department
Pharmacology
Type
Schools of Dentistry
DUNS #
208469486
City
Rochester
State
NY
Country
United States
Zip Code
14627
Radcliffe, Pheona M; Sterling, Carol R; Tank, A William (2009) Induction of tyrosine hydroxylase mRNA by nicotine in rat midbrain is inhibited by mifepristone. J Neurochem 109:1272-84
Xu, Lu; Sterling, Carol R; Tank, A William (2009) cAMP-mediated stimulation of tyrosine hydroxylase mRNA translation is mediated by polypyrimidine-rich sequences within its 3'-untranslated region and poly(C)-binding protein 2. Mol Pharmacol 76:872-83
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Chen, Xiqun; Xu, Lu; Radcliffe, Pheona et al. (2008) Activation of tyrosine hydroxylase mRNA translation by cAMP in midbrain dopaminergic neurons. Mol Pharmacol 73:1816-28
Xu, Lu; Chen, Xiqun; Sun, Baoyong et al. (2007) Evidence for regulation of tyrosine hydroxylase mRNA translation by stress in rat adrenal medulla. Brain Res 1158:1-10
Osterhout, Cheryl A; Sterling, Carol R; Chikaraishi, Dona M et al. (2005) Induction of tyrosine hydroxylase in the locus coeruleus of transgenic mice in response to stress or nicotine treatment: lack of activation of tyrosine hydroxylase promoter activity. J Neurochem 94:731-41
Yoshimura, Reiji; Xu, Lu; Sun, Baoyong et al. (2004) Nicotinic and muscarinic acetylcholine receptors are essential for the long-term response of tyrosine hydroxylase gene expression to chronic nicotine treatment in rat adrenal medulla. Brain Res Mol Brain Res 126:188-97
Sun, Baoyong; Chen, Xiqun; Xu, Lu et al. (2004) Chronic nicotine treatment leads to induction of tyrosine hydroxylase in locus ceruleus neurons: the role of transcriptional activation. Mol Pharmacol 66:1011-21
Thiruchelvam, Mona; McCormack, Alison; Richfield, Eric K et al. (2003) Age-related irreversible progressive nigrostriatal dopaminergic neurotoxicity in the paraquat and maneb model of the Parkinson's disease phenotype. Eur J Neurosci 18:589-600

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