Characterization of Ocrl in Drosophila melanogaster

Disease modelling has enabled researchers to study a wide range of human diseases in the laboratory, overcoming many challenges. Parkinson Disease (PD) is a progressive neurodegenerative disorder that affects 1 to 2% of the human population over 65 years old, influencing cognitive ability and motor function. It is characterized by the inadequate function or the loss of dopamine-producing neurons of the substantia nigra pars compacta in the human midbrain. Impairment of several genes has been associated with disease progression. Recently, a polymorphism in Oculocerebrorenal Syndrome of Lowe protein (Ocrl), was identified as a risk factor for PD. As Ocrl is very well-conserved between mammals and insects, I have used D. melanogaster to create an Ocrl-dependant model of human PD. Ocrl is the D. melanogaster orthologue of human Ocrl, a PtdIns(4,5)P2 phosphatase encoding gene in which mutant forms can result in the X-linked disorder known as Oculocerebrorenal Lowe Syndrome. Directed manipulation of the single D. melanogaster version of Ocrl in neurons that include dopaminergic neurons was performed in order to produce an in vivo model of the development and progression of a unique version of PD. The directed loss of function of Ocrl in dopaminergic neurons, through the use of RNAi, resulted in a decreased locomotor ability and median lifespan of the flies over time. In complementary experiments, the directed interference of Ocrl expression in the developing eye, led to a reduction in the number of ommatidia and interommatidial bristles. Overexpression of Ocrl using D42 Gal4 and ddc Gal4 decreased lifespan, locomotor ability, the number of ommatidia and interommatidial bristles and increased lifespan by using TH Gal4. Crossing Ocrl with recombinant Ddc-GAL4/CyO; UAS-park RNAi/TM3 reduced lifespan overtime. Further investigation of Ocrl and its role in human disease progression is needed and crucial to our understanding of new therapeutic approaches for research into human disease