Microglia have been implicated in the progressive nature of neurodegenerative diseases, particularly Parkinson’s disease (PD). Several environmental toxicants are associated with oxidative stress, such as paraquat, and have been linked to increased incidence of PD, but the mechanisms are poorly understood. Our research group studies the mechanisms through which reactive oxygen species (ROS) reprogram microglia to become a neurotoxic phenotype.
As CNS sentinels, microglia detect and respond to a diverse array of stimuli in the brain, including environmental toxins, bacterial toxins, cytokines, neuron damage, and disease proteins, where the activation state can be characterized as a pro-inflammatory (M1) and/or alternative (M2) response. Accumulating evidence indicates that a neurotoxic microglial phenotype occurs when microglia M1 activation is dysregulated, which we define as an enhanced M1 pro-inflammatory response with impaired resolution (M2 response). While several studies indicate that ROS amplify the pro-inflammatory response without the ability to initiate the M1 response in microglia, the mechanisms are unknown. Using immuno-spin trapping, the Block Lab has begun to explore the potential targets (protein radicals) in microglia modified by ROS to result in a M1 polarized, dysregulated, and neurotoxic microglial response.