Characterization of a LRRK2 (PARK8) homologue in Drosophila melanogaster

Nightingale, Michael Craig (2023) Characterization of a LRRK2 (PARK8) homologue in Drosophila melanogaster. Masters thesis, Memorial University of Newfoundland.

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Abstract

Parkinson Disease is the second-most common neurodegenerative disorder and is caused by a loss of dopamine-producing neurons in the substantia nigra region of the brain. The disease is characterized by symptoms of involuntary tremors, weakness, and a characteristic posture in which the trunk of the body is bent forward. Variations in the LRRK2 gene may be responsible for up to 13% of monogenic and 5% of sporadic cases of the disease, which would make it one of the most common causes of Parkinson Disease. Despite the prevalence of LRRK2-linked cases of Parkinson Disease, the role that LRRK2 plays in Parkinson Disease pathogenesis is still unclear. This study focuses on the examination of the Drosophila melanogaster Lrrk gene, a homologue of the human LRRK2 gene, in order to gain a better understanding of LRRK2 and its role in Parkinson Disease. Bioinformatic comparison of the human LRRK2 and Drosophila Lrrk protein suggests that the functions of these proteins are similar in both humans and Drosophila. Examination of a Drosophila Lrrk loss-of-function mutation was found to result in loss of climbing ability at eclosion, which indicates the possibility of abnormalities in dopamineproducing neurons, as well as other phenotypes that suggest an upregulation of dopamine synthesis. A P-element insertion into the promoter region of the Lrrk gene was found to induce the sporadic formation of melanotic tumors in Drosophila larvae, further supporting a possible link between dopamine synthesis and the Lrrk gene. As dopamine-producing neurons are at risk of cell death in Parkinson Disease, these results suggest a possible link between LRRK2 and regulation of dopamine synthesis in Parkinson Disease pathogenesis. In addition to links to dopamine synthesis, the phenotypes suggest the possibility of changes in Notch signalling. Finally, Drosophila Lrrk was found to interact with Gal4-induced toxicity when Gal4 was expressed through use of the Ddc:Gal4 driver, which supports a possible role for Lrrk in protein degradation.

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