Heather Klintworth

Project title: Molecular Mechanisms of Dopaminergic Neuron Death

Degree: PhD | Program: Environmental Toxicology (Tox) | Project type: Thesis/Dissertation
Completed in: 2010 | Faculty advisor: Zhengui Xia


Parkinson's disease (PD) is characterized by a loss of dopaminergic neurons in the substantia nigra that results in motor impairments in PD patients. The mechanisms of dopaminergic cell death are still unclear. Here, I aim to elucidate the molecular mechanisms of several PD models. Rotenone, paraquat, and MPTP are toxicants known to recapitulate some of the key features of PD. I determined that JNK signaling was required for rotenone-induced apoptosis and that bFGF protected against cell death via activation of ERK1/2 and PI3-kinase. JNK activation is also found in paraquat and MPTP models of PD, indicating that JNK phosphorylation may be a common mechanism in dopaminergic degeneration. Other cell types in the brain are known to mediate dopaminergic toxicity and I further examined the role rotenone and paraquat play in the brain's inflammatory response by microglia. I found that rotenone and paraquat did not directly activate microglia to stimulate release of inflammatory factors. Lastly, rotenone, paraquat, and MPTP are thought to cause dopaminergic cell death via inhibition of mitochondrial complex I. However, recent studies have challenged this theory. In my last set of experiments I used a MPTP in vivo model to test this hypothesis. While the data was inconclusive, I gained valuable experience in working with in vivo neurodegenerative models.