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.
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