This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Parkinson's Disease (PD) is characterized by the sustained loss of nigrostriatal dopaminergic neurons leading to motor impairment and dementia. Generally of unknown etiology, a role for oxidative stress is a common component of disease pathogenesis. PD is accompanied by activation of brain-resident mononuclear phagocytes (MP; microglia) and astrocytes. Activation of microglia is accompanied by NADPH-oxidase mediated production of reactive oxygen species (ROS). NADPH-oxidase is upregulated in PD and its expression coincides with activated microglia. Astrocytes play a major role buffering the ROS due to high glutathione (GSH) content and may also regulate ROS production by microglia. The GSH system is the major redox buffer in brain, and decreased GSH content is the first indicator of oxidative stress in PD. Microglial ROS production involves massive electron efflux, necessitating compensatory ion movement. The overall aim of this study is to characterize the role of ion currents in the generation and regulation of ROS release by murine microglia, and the response of the glutathione system to this local increase in oxidative stress. We believe that understanding these regulatory mechanisms could provide therapeutic tools for slowing or stopping the progression of PD by modulating ionic currents crucial for ROS generation. Results will be ocmpared between isolated MP cultures and co-cultures of MP with astrocytes. Co-cultures represent a first step in the reconstitution of the in vivo relationship between glial cells, towards establishing laboratory models of human neurodegenerative diseases. The long term plan is to develop viable models to study redox biology in PD.
The specific aims are: (1A) Determine the relative role of ion channels in the generation of ROS by isolated MP; (1B) Characterize the response of the glutathione system to ROS-generating stimulation of MP; (2A) Determine how ROS production by MP is regulated by astrocytes; (2B) Determine how the response of the glutathione system to ROS generating stimulation of MP is regulated by astrocytes. Depending on the status of microglial and astrocyte populations, the balance between ROS production and ROS protection could be shifted towards either a cumulative neurotoxic or neuroprotective profile. A better understanding of the interactions between microglia and astrocytes in the context of redox regulation is vital to understanding the progression of neurodegenerative diseases such as PD.
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