Furthermore, it is also probable that numerous previously identified WFA-induced molecular effects

attenuated in dopaminergic synaptosomes isolated from doxinduced animals that had been co-treated with deprenyl or EUK- February Elevated MAO-B & PD Pathology February Elevated MAO-B & PD Pathology r synaptosomes probed with TH, GABA or SNAP- Increases in There are no reports, to our knowledge, regarding the effectiveness of PDGF antagonism in either the classical astrocytic MAO-B activity results in increased local microglial activation in the SN Data from our mitosox red studies not only suggested that SN dopaminergic neurons display an increase in oxidative stress following astrocytic MAO-B elevation, but also in the activated local SN microglial cells. This is likely a secondary effect subsequent to dopaminergic SN neurodegeneration triggering local microgliosis. Degeneration of SN dopaminergic neurons in PD has been observed to be accompanied by local microglial activation. It has also been noted post-mortem in both humans and primates exposed to MPTP. It is detected in the chronic mouse rotenone model prior to appearance of the February Elevated MAO-B & PD Pathology Mean pixel intensity per cell ND D DD DEUK Total pixel fluorescence per cell Confocal quantitation of relative mitosox-red fluorescence intensity in SN DA neurons in untreated or dox-treated transgenic mice in the absence or presence of deprenyl or EUK- dopaminergic lesion and during selective SN dopaminergic neurodegeneration in the spontaneous weaver mouse mutant. We performed immunochemistry to evaluate microglial activation in our induced MAO-B transgenics via Iba Increases in astrocytic MAO-B activity results in decreased locomotor movement Finally, astrocytic increases in MAO-B in our model were found to correlate with a significant inhibition of locomotor function. Open field analysis of dox-treated mice revealed a significant difference in locomotor behavior in induced versus uninduced transgenics. After treatment with dox alone for two weeks, induced mice displayed a, an age-related increase in MAO-B enzyme activity. Our results suggest that perhaps the elevation of MAO-B to aging levels in the young animals was sufficient on its own to produce significant cell loss and that the additional stress of an aging brain contributed marginally to this effect. Observed cell loss was accompanied by increased mitochondrial oxidative stress and selective decreases in mitochondrial complex I activity in these cells along with local microglial activation all of which we assume contribute to subsequent cell death. These pathological alterations were found to correlate with a significant decrease in locomotory behavior. Our data, taken in total, demonstrates that elevations in levels of astrocytic MAO-B activity results in several of key pathological hallmarks of Parkinson's disease. ROS produced by MAO-B-expressing astrocytes can be released into the extracellular environment and, due to its high membrane permeability, diffuse into neighboring cells. Within dopaminergic neurons, it can oxidize dopamine to DACHR which can interact with electrons at the auto-oxidizable site of mitochondrial complex I at a higher affinity than oxygen itself producing DACR radical. Electrons can then be transferred from DACR radical to oxygen resulting in re-reduction of DACR to DACHR and production of superoxide as part of an ongoing redox cycling event. These events are shown schematically in Discussion Increased brain MAO-B levels have been hypothesized to play a role in neuropathies associated with PD however direct proof of a causative role has been thus far lacking. In this study, we demonstrate t