Text

theses

Parkinson disease (PD) is the second most common neurodegenerative disorder of aging worldwide. There is mounting evidence that both genetic and environmental factors contribute to the development of PD. The main hallmarks of PD pathology include loss of dopamine neurons in the substantia nigra pars compacta (SNc), activation of microglia, production of pro-inflammatory cytokines, and accumulation of oxidized lipids and proteins. Epidemiologic studies suggest that exposure to pesticides may contribute to the development of PD, particularly in individuals with a genetic polymorphism in the Multidrug Resistance Transporter 1 (MDR1) which removes chemicals from the brain. The herbicide paraquat is used to study features of PD in rodents, namely dopamine neuron loss and microglial activation. The work presented in this dissertation examines the role that the MDR1 efflux transporter plays in preventing neuronal death from paraquat-induced toxicity, as well as immunologic factors that modulate this protective function. Following exposure to a single dose of paraquat, mice lacking the Mdr1a/1b genes have extensive dopamine neuron loss and microglial activation in the SNc, whereas wild-type mice require at least two doses. It is hypothesized that MDR1 is an efflux transporter for paraquat thereby preventing paraquat accumulation and toxicity in the brain. Experiments using an MDR1-transfected cell line or human cerebral endothelial cells naturally expressing MDR1 demonstrate that accumulation of paraquat is reduced in cells with functional MDR1. Work in this dissertation also investigates the regulation of Mdr1 and other transporters in microglia. Activation of microglia with lipopolysaccharide (LPS) leads to the down-regulation of Mdr1 and Bcrp and up-regulation of Mrp1 and Mrp5 transporters. Using fluorescent substrates, it is observed that LPS activation of microglia reduces the function of Mdr1 and Bcrp. Lastly, the mechanisms that regulate Mdr1 in activated microglia are explored. Using inhibitors and activators of several cellular pathways, including NF-κB, Nrf2, and cytokines, it is found that Mdr1 is strongly influenced by TNF and NF-κB pathways. This thesis demonstrates the ability of the Mdr1 transporter to protect against pesticide-induced neural injury and characterizes the role of inflammatory factors in regulating Mdr1 expression and function in microglia and the blood-brain barrier.

ETD_6145

Ph.D.

Includes bibliographical references

by Christopher Gibson

doi:10.7282/T3377BF2

ETD doctoral

The author owns the copyright to this work.