Role of dopamine in alpha-Syn-mediated neurodegeneration

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DESCRIPTION (provided by applicant): Since the synapse is a functional building block of the brain, defects in, or loss of, specific synaptic signaling/modulation consequently underlies neurological disorders such as Parkinson's disease (PD). Therefore, our interests are to understand the cellular and molecular mechanisms underlying selective degeneration of dopaminergic (DA) neurons and synapses. Among the proposed underlying causes of DA cell death, oxidative damage is thought to play an important role. Ironically, neurotransmitter dopamine itself can become a source of oxidative stress and consequently contribute to the selective DA cell death in PD. This study aims to reveal mechanisms underlying dopamine's ability to mediate alpha-synuclein-induced neurodegeneration. We will employ molecular genetic, immunocytochemical and amperometrical approaches applied to a variety of transgenic fly lines and primary neuronal cultures as a model system. The results of our experiments will contribute to our understanding of the molecular mechanisms of how alpha-synuclein induces disruption of DA homeostasis, resulting in elevated levels of cytoplasmic DA and eventually leading to specific neuronal death. The high degree of conservation between vertebrates and invertebrates in terms of the basic mechanisms important in DA modulation, suggests that our studies in Drosophila will be important in guiding development of rational treatment strategies aimed at restoring dopamine function/homeostasis that has been disrupted in Parkinson's disease patients. In addition, amperometric recordings of synaptic DA release and cytoplasmic DA concentrations will be very useful not only to characterize the relationship between DA homeostasis and specific neurodegeneration, but also to study DA signaling mechanisms mediating learning/memory and drug addiction.