Dr. Maguire-Zeiss' laboratory is focused on understanding the molecular mechanisms involved in age-related neurodegenerative diseases. In particular, we are investigating the vulnerability of the nigrostriatal pathway in Parkinson’s disease (PD). Although the etiology of PD is currently unknown it is thought to involve both genetic vulnerability and environmental toxicants. We are currently following several lines of investigation with regard to PD pathogenesis. At the most basic science level we are studying the role of dopamine and alpha-synuclein in PD. Overexpression of and mutations in alpha-synuclein have been linked to familial PD. In addition, changes in the structure of this protein have been identified in toxicant models of PD. Utilizing both in vitro and in vivo models we are studying the effect of dopamine and dopamine quinone formation on alpha-synuclein protein conformation. We are also developing therapeutic interventions that will both alter alpha-synuclein toxic conformer formation and prevent cell death. Interference with alpha-synuclein aggregate formation or dissolution of existing aggregates is hypothesized to attenuate the pathophysiology of PD. To address this hypothesis we are employing an approach that utilizes humanized single chain antibodies (scFvs) that recognize structural epitopes on alpha-synuclein. In addition, to address the combination of genetic vulnerability and neurotoxicant exposure on PD pathogenesis we are utilizing transgenic mice that overexpress alpha-synuclein and chronic exposure to neurotoxicants. Using this paradigm we are studying the role of microglia, glutathione peroxidase and oxidative stress in cellular dysfunction.


Selected Publications:

• Su X, Federoff HJ, Maguire-Zeiss KA.: Mutant alpha-Synuclein Overexpression Mediates Early Proinflammatory Activity. Neurotox Res. 2009