Parkinson disease (PD) is caused by a progressive loss of the dopamine (DA) neurons in the substantia nigra pars compacta (SNc). Although the etiology of PD is still unknown, there is increasing evidence that it is a complex disorder influenced by a combination of genetic and environmental factors affecting key signaling pathways in DA neuronal cell function. To find new or improve current therapies for PD, it is necessary to understand the physiology of normal cell function and the pathophysiology of degeneration. In an attempt to gain further insight into the molecular events in PD pathogenesis, we recently determined the gene expression profiles of DA neurons from the SNc of normal and idiopathic PD patient's brains isolated by laser microdissection (LMD). Our data showed a dysregulation of several groups of genes, which are involved in the pathogenesis of PD and provided a """"""""molecular fingerprint"""""""" of PD-affected late stage DA neurons. Dysregulated gene expression is a major factor in PD pathogenesis, however many of the mechanisms and factors involved in these processes are not known. Our proposal will explore whether micro (mi)RNAs are involved in these processes. miRNAs are a recently discovered class of small 18-23 nucleotide non-coding RNA molecules that have been shown to regulate target gene expression in various organisms. In the nervous system, they are involved in the development, function and identity of neuronal cell populations including the DA phenotype. In addition, miRNAs have been implicated in neurodegeneration. Here, we hypothesize that specific miRNAs may be involved in the downregulation of PD-related gene expression and, therefore, might play a role in PD pathogenesis and potentially represent novel targets for therapy development. To corroborate our hypothesis, we have generated preliminary data demonstrating differential miRNA expression profiles on laser microdissected DA neurons from normal subjects and PD patient's brains using highly sensitive high through-put Megaplex TaqMan(R)-based real-time PCR. We propose to use this technology to determine a complete miRNA expression profile on DA neurons from the same normal and PD patients'brains as in our previous study and to identify PD-specific miRNAs and their potential mRNA targets that are involved in key pathways of PD pathogenesis. We believe that results from these studies will enhance our understanding of the molecular mechanisms of DA cell function and will have high potential for the development of novel treatments for PD.
Parkinson disease (PD) is caused by the progressive loss of midbrain dopamine (DA) neurons and gene expression profiling on these cells have demonstrated a prominent down-regulation of several groups of genes affecting key signaling pathways in the pathogenesis of PD. MicroRNAs (miRNAs) introduce a novel concept of regulatory control over gene expression and have been implicated in the function and identity of neuronal cell populations including DA neurons. To further understand the pathology of PD and find new therapeutic targets, we propose to identify and characterize miRNAs involved in the function and dysfunction of the DA neuronal phenotype.
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