? Parkinson's disease is characterized by a progressive degeneration of the dopaminergic nigrostriatal projection. There is currently no therapy available that can alter the course of the disease. Recent evidence from animal models indicates that neurotrophic and growth factors may possess disease-modifying characteristics; particularly glial cell line-derived neurotrophic factor (GDNF) for the nigrostriatal projection. Prior studies demonstrate that GDNF provides protection to dopamine neurons exposed to neurotoxins, such as 6-hydroxydopamine (6-OHDA), which mimics the degeneration of the nigrostriatal projection in PD. It is not yet clear how GDNF exerts its neuroprotective effects. A challenge in interpreting these studies involves the choice of biomarker for nigrostriatal integrity. Ideally, the marker should not be influenced by the symptomatic treatments or by resultant changes in DA activity. Ongoing work in our laboratory has developed a quantitative assay to detect expression levels of the vesicular monoamine transporter type-2 (VMAT2), which does not undergo activity-dependent regulation in intact animals. The present series of experiments address the overall hypothesis that VMAT2 is an objective biomarker for the nigrostriatal projection in animal models of PD and neuroprotection by GDNF. More specifically, we will test the following hypotheses: (1) VMAT2 expression is not influenced by the administration of GDNF in the intact rat; (2) VMAT2 will detect GDNF neuroprotection in the rat 6-OHDA lesion model of PD; (3) acute GDNF will have lasting neuroprotective effects. This research will contribute to the development of an objective biomarker that will indicate nigrostriatal integrity and expedite the search for an effective disease-modifying treatment for Parkinson's disease. ? ?
