Further characterization of PGC-1α, PARIS and VPS13C

Abstract

Parkinson Disease (PD) is a neurodegenerative disease characterized by the loss of dopaminergic neurons in the substantia nigra of the brain and is often accompanied by the presence of Lewy bodies in surviving neurons. A number of genes have been identified to contribute, when expression is altered, to the pathogenesis of PD. This study focuses on PGC-1α, PARIS, and VPS13C which have all been implicated in pathways involved with mitochondrial biogenesis and lipid transport; two important processes that have been implicated in PD. Using Drosophila melanogaster as a model organism, I have investigated the consequences of altered gene expression using the homologues spargel (srl), Paris, and Vps13 to further characterize the role that alterations to the expression of these genes play in disease and ageing. Most notably, this study found that enhanced expression of srl decreased longevity and locomotor ability when expressed in the motor neurons. Reduced expression of srl was found, in some instances, to increase longevity when expression was directed to the motor neurons, and glial cells. The overexpression of Paris in the motor neurons increased longevity, while overexpression in both the motor neurons and glial cells improved locomotor ability. Investigating altered Vps13 expression yielded varying results. However, this study demonstrated that when expression of Vps13 is enhanced in the motor neurons, dopaminergic neurons, and glial cells, longevity is decreased. Additionally, inhibition of Vps13 in the motor neurons, dopaminergic neurons, and glial cells can increase longevity in Drosophila. These results help to further characterize these genes and their respective roles in models of human disease and ageing. I evaluated UAS-LUC-RNAi as a negative control for RNAi, as well as the potential for enhanced longevity using three Gal4 lines which are new to the Staveley research group. Most notably, this study determined that UAS-LUC-RNAi is a suitable control for RNAi with the Gal4 in longevity experiments and should be used in future studies. As well, C380-Gal4, is not a suitable activating transgene for expression in the motor neurons during longevity experiments as this reduced lifespan when driving the expression of a lacZ control.