Reduced vesicular catecholamine storage mediates oxidant-induced neurotoxicity

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DESCRIPTION (provided by applicant): Parkinson's disease (PD) is a debilitating neurodegenerative disorder, which is characterized by the loss of dopamine (DA) in the putamen and DA producing neurons of the substantia nigra, resulting in motor disturbances such as tremor, rigidity, postural instability and bradykinesia. PD is currently thought to be caused by a combination of environmental and genetic factors. Current therapies include L-DOPA administration, MAOB inhibitors, and DA agonists, which all increase the amount of DA signaling in the brain. Normally, DA is highly regulated within the neuron; the dopamine transporter (DAT) mediates selective uptake of dopamine from the synapse, adjusting the magnitude and duration of neuronal signaling. The vesicular monoamine transporter (VMAT2) then pumps cytosolic DA into vesicles for exocytotic release. VMAT2 is important in mediating neuronal susceptibility to cellular damage, particularly via the prevention of oxidative stress. VMAT2 normally sequesters catecholamines, protecting against neuronal damage; however, when VMAT2 expression is reduced, DA and NE can become oxidized in the cytosol, inducing endogenous oxidative damage. During periods of DA handling dysfunction, cellular antioxidant defenses are activated; but when these defenses fail, neurodegeneration can occur. In order to study the role of VMAT2 in PD, many groups have tried to generate VMAT2 KO mice, but completely ablating VMAT2 is lethal. Previously, our laboratory has shown that mice with a 95% genetic reduction in VMAT2 (VMAT2 LO) display progressive loss of striatal DA, L-DOPA responsive behavioral deficits, synuclein aggregation, and nigral dopamine cell loss. We hypothesize that the progressive damage in the VMAT2 deficient mice is due to increased oxidative stress as the mice age. The goal of this research is to elucidate the role of VMAT2 in the development of PD, more specifically, the ability of VMAT2 to modulate neuronal redox state in the presence of catecholamine mediated toxicity. I will test this hypothesis by 1) determining if there is an agedependent altered redox state in VMAT2 LO mice, 2) investigating if L-DOPA administration exacerbates this altered redox status, and 3) determining the role of NE in oxidant-induced neurodegeneration in the VMAT2 LO mice. Given the increasing importance of oxidative stress related research, especially as it pertains to neurodegeneration, this research has the potential to illuminate possible endogenous mechanism for the development of PD in humans. Furthermore, any oxidative mechanisms that are uncovered through this research can serve as the link between genetic and environmental factors in PD disease progression.