Effect of co-expression of alpha-synuclein and leucine-rich repeat kinase 2 on the hallmark features of Parkinson’s disease in Drosophila melanogaster

Abstract

Alpha-synuclein (SNCA) and leucine-rich repeat kinase 2 (LRRK2) are involved in multiple pathways important for cellular function, implying potential interplay. It is thus important to study the combined effect of SNCA and LRRK2 on the cellular processes involved in the pathophysiology of PD. Mutations in the genes encoding the two proteins have been linked to an autosomal dominant form of Parkinson’s disease (PD). This study will help in unearthing underlying mechanisms that might be driven by both proteins working in a synergistic manner. We, hereby developed a model in Drosophila melanogaster by co-expressing SNCA and LRRK2 in all neurons, glia, and dopaminergic neurons to determine the interplay between SNCA and LRRK2 which will help us to better understand the pathophysiology of PD. We expressed either individually or co-expressed human SNCA, human wild-type LRRK2, and human mutated form of LRRK2 named LRRK2- G2019S in all neurons, glia, and dopaminergic neurons and evaluated for differences in life span, locomotion, and dopaminergic cell death. The individual expression of SNCA, LRRK2, and LRRK2-G2019S in all neurons, glia, and dopaminergic neurons was shown to cause selective loss of dopaminergic neurons, locomotor dysfunction, and early mortality. Co-expression of SNCA with wild-type and mutant LRRK2 in the same set of cells caused a more severe form of fly mortality, locomotor dysfunction, and dopaminergic neuronal death than an individual expression of the proteins. This study indicated that expression of both SNCA and LRRK2 exhibited a synergistic effect, and both proteins might be involved in molecular pathways leading to PD-associated neurodegeneration. The Drosophila model recapitulated the key features of PD and might take us one step closer to understanding the disease and serve as a therapeutic screen for PD-associated interventions.