The etiology of Parkinson?s disease (PD) is currently unknown and treatment is unable to haltdisease progression. Microglia, the innate immune cells of the brain, are implicated in PDprogression, but the mechanisms driving continuous and pathologically activated microglia arepoorly understood. Environmental factors are associated with PD etiology and can chronicallyactivate microglia to cause dopaminergic (DA)neuron damage. Microglial NADPH oxidase andreactive oxygen species may have a role in deleterious microglial activation, but how theyregulate microglial function is largely unknown. Our overarching hypothesis is thatenvironmental insult (MPTP/MPP+ and LPS) causes chronic neuroinflammation andprogressive DA neuron damage through changes in microglial protein radical biochemistry.Beginning with the NF?? radical, we will test the specific hypothesis that LPS and MPTP/MPP+-induced NADPH oxidase activation causes microglial protein radicals that drive progressiveneuroinflammation and DA neurotoxicity by: A) enhancing the production of neurotoxic pro-inflammatory factors (microglial priming); B) mediating the failure of microglia to resolve the pro-inflammatory response. Preliminary data indicate that microglia respond to MPP+-induced DAneuron-injury signals and LPS by changing their protein radical profile and increasing thecytosolic NF?? p50 radical. Thus, beginning with the NF?? radical, the specific aims are to: 1)identify the proinflammatory and priming characteristics of NADPH oxidase-derived proteinradicals (NF?? p50 radical); 2) define the role of astrocyte-microglia interactions on NF?? p50radical formation, neuroinflammation, and microglia-mediated DA neurotoxicity; 3) characterizethe role of the NADPH-oxidase derived NF?? p50 radical in progressive DA neuron damage invivo; 4) determine the neuroprotective and anti-inflammatory effect of inhibiting NF?? p50radical formation and function. We expect to systematically demonstrate for the first timethat environmental insult causes protein radicals in microglia that fuel progressive DAneurotoxicity and identify these markers of deleterious microglial activation (i.e. NF?? p50).These studies will define a new avenue of research in PD pathogenesis and the role ofenvironmentally-induced oxidative stress in neurodegenerative disease. Finally, this work willprovide valuable insight into the identification and timing of novel therapeutictargets capable of slowing PD progression.
These studies will define a new avenue of research in Parkinson's disease pathogenesisand the role of environmentally-induced oxidative stress in neurodegenerative disease.Finally; this work will provide valuable insight into the identification and timing of noveltherapeutic targets capable of slowing Parkinson's disease progression.
Showing the most recent 10 out of 12 publications
