Parkinson's disease is a common neurological disorder, the symptoms of which are caused primarily by a loss of dopamine neurons in the substantia nigra and reduced dopamine in the striatum. The transcription factor Nurr1 is necessary for normal dopamine neuron development as demonstrated by a failure of dopamine neurons to develop properly in Nurr1-null homozygous mice. Nurr1 also appears to function in maintaining normal dopamine synthesis and dopamine neuron survival as mice with a single deletion of the Nurr1 gene are impaired in both parameters. Additionally, the expression of Nurr1 has been shown to fluctuate as a result of changes in electrical activity and after treatments that can affect the activation of dopamine autoreceptors. The relative contribution of these factors on Nurr1 expression have not been determined. Based on this data, we hypothesize that increasing neuronal activity and inhibition of dopamine autoreceptors will increase Nurr1 expression in dopamine neurons. Furthermore, we hypothesize that attenuating Nurr1 expression will attenuate target genes of Nurr1, dopamine synthesis and dopamine neuron survival. Currently, little is known about the mechanism(s) that regulate Nurr1 expression in adult dopamine neurons, how changes in Nurr1 affect dopamine synthesis or how Nurr1 functions in dopamine neuron survival. The specific aims of the current proposal are 1) to establish the conditions that control Nurr1 expression in dopamine neurons in vivo by comparing the contributions of changes in neuronal activity and dopamine autoreceptor activation by stimulating or inhibiting activity alone or in combination with a dopamine receptor agonist or antagonist introduced via reverse microdialysis, and 2) to identify the extent by which Nurr1 controls dopamine neuron function by measuring changes in dopamine neuron gene expression and parameters of dopamine synthesis and changes in dopamine neuron survival in conditions of attenuated Nurr1 expression (antisense oligonucleotides and aging in Nurr1-null heterozygous mice). By using a combination of laser capture microdissection with gene expression technology of quantitative real-time PCR and eXpress profiling multiplex capillary electrophoresis based quantitative PCR; these experiments will demonstrate the utility of these techniques for investigating the role of transcription factors in the regulation of neurotransmission genes and specifically, the regulation of dopamine neurotransmission genes by Nurr1. The long term goal is to better understand the role of transcription factors in the function and survival of dopamine neurons as they relate to the pathogenesis of Parkinson's disease. The current proposal will ascertain how Nurr1 expression in dopamine neurons is regulated in vivo and how Nurr1 functions to regulate dopamine synthesis and survival of dopamine neurons. This data will aid in determining the potential for targeting Nurr1 expression as a means to elevate dopamine synthesis and dopamine neuron survival as a treatment of Parkinson's disease. PUBLIC HEALTH RELEVANCE Since Parkinson's disease is caused by a loss of neurons that make dopamine; the current treatments consist of drugs that replace dopamine. These treatments, however, do not delay the loss of dopamine neurons or the progression of the disease. By understanding how specific genes control the production of dopamine and keep dopamine neurons from dying, new treatments targeting the expression of these genes can be developed that both treat Parkinson's disease symptoms and/or delay the progression of this disease. [unreadable] [unreadable] [unreadable] [unreadable]
NIH ExPorter
NIH ExPorter