The biological interactions of the Drosophila orthologue of LRRK-2 in the pathogenesis of Parkinson's disease. (360G-Wellcome-086406_Z_08_Z)

Parkinson s disease (PD) is a common progressive neurodegenerative disease with extra-pyramidal symptoms and cognitive decline, due to the progressive loss of dopaminergic neurons in the substantia nigra whose pathogenesis is largely unknown. Current drug treatments relieve symptoms but do not prevent neuronal cell loss. Analysis of single gene mutations that cause inherited forms of PD has advanced our understanding of the pathogenesis of PD. Mutations in the leucine-rich repeat kinase 2 (LRRK2 ) gene account for a large proportion of dominantly inherited and sporadic disease. The biological function(s) of LRRK2 are unknown and it is unclear whether LRRK2-related PD is caused by a gain or loss of function mechanism. Key goals of the proposed project are: 1. To understand the normal biology of wild type LRRK2 and its Drosophila orthologue dLrrk in relation to the pathogenesis of LRRK2-related PD. 2. To identify novel physical and genetic interactors of wild type LRRK2, and genetic in teractors of dLrrk that modulate the loss-of-function of dLrrk in a Drosophila model, in order to understand the pathways in which these proteins participate. These approaches will reveal the in vivo role of dLrrk and LRRK2, and identify potential novel therapeutic targets to prevent neurodegeneration in PD.