Mechanisms of TRP-channel mediated dopaminergic degeneration in C. elegans

Abstract

One of the most common manifestations of dopaminergic degeneration in humans is in Parkinson’s Disease (PD). Although dopaminergic degeneration affects a significant portion of the aging population, the pathways and mechanisms underlying it have not yet been elucidated. The Doitsidou lab has recently established a model of dopaminergic degeneration in Caenorhabditis elegans. In this model, a Transient Receptor Potential (TRP) channel (TRP-4) has mutated and results in a gain of function. Based on the morphology of the dopaminergic neurons, the overactive channel is believed to be activating a necrotic cell death pathway. This thesis aims to identify the pathways relevant to TRP-4 mediated dopaminergic de-generation in Caenorhabditis elegans. It takes a two-pronged approach, comparing TRP-4 degeneration to other models of neurodegeneration and conducting a forward genetic screen to identify novel candidates. Through these approaches, the nature of TRP-4 degeneration has been further eluci-dated. The results gathered in this thesis explore the involvement of lysosomal acidifica-tion through the V-ATPase pump in dopaminergic cell death and are not conclusive as to whether or not the V-ATPase pump plays a role in TRP-4 induced degeneration. The lysosomal biogenesis pathway is implicated in dopaminergic degeneration in the TRP-4 model. Differences in lysosomal morphology in dopaminergic neurons are established between the wild type and degenerating states. Finally, three full and three partial sup-pressors of degeneration were discovered through the automated forward genetic screen. Together, this thesis brings insight into intracellular the mechanisms underlying a novel, TRP-channel based model of dopaminergic degeneration. 3