Investigation into the effect of LRRK2-Rab10 protein interactions on the Proboscis Extension Response of the fruit fly Drosophila melanogaster

Parkinson’s Disease (PD) is a debilitating disease which affects 1% of the population worldwide and is characterised by stiffness, tremor and bradykinesia. PD is a complex disease with many suspected genetic and environmental causes, and it is critical to understand all the pathways involved in disease progression to develop effective therapies for PD, which currently has no cure. A kinasecoding gene, LRRK2 has emerged as a focal point for much PD research, particularly PD-associated SNP LRRK2-G2019S, which leads to LRRK2 overactivity. Rab proteins, a series of small GTPases, have been identified among the proteins phosphorylated by LRRK2. These interactions may be modelled in the fruit fly Drosophila melanogaster. Using optogenetics in the fly, this project investigates the relationship between the LRRK2-G2019S and Rab10 interaction, and the speed and degree of tremor of Proboscis Extension Response (PER) by triggering a PER in fly lines of different genotypes. Significant bradykinesia in Rab10 null flies which was not recreated in flies with dopaminergic neuron Rab10RNAi suggests that the bradykinesia PER phenotype is caused by off-target effect of Rab10-KO in another tissue of the fly than the dopaminergic neurons. Over-expression of Rab10 in dopaminergic neurons of flies also expressing LRRK2-G2019S produced resting tremor and inability to fully extend the proboscis.