Understanding the role of LRRK2 in Parkinson’s disease

The most common genetic cause of Parkinson’s disease (PD) is a mutation in the LRRK2 gene, G2019S. We have developed a new fly model, which exploits the homology of gene and visual organization between fly and human. It shows rapid decline in electroretinogram performance with G2019S expression, but not with other mutations in LRRK2. This loss of visual function is most marked when G2019S is expressed in the dopaminergic neurons. Remarkably, when G2019S is expressed in dopaminergic neurons it is the non-dopaminergic photoreceptors which are most affected, indicating a spreading pathology. This is made worse by increasing neural activity, either by turning the light on and off repeatedly, or by genetic manipulations of the dopaminergic neurons. We will use the extensive fly genetic toolbox to test the function of G2019S as a dominant negative kinase mutation, and to examine the role of neural activity in accelerating the speed of degeneration. We will support this by using drug application (L-DOPA, kinase inhibitors, glycolytic upregulation). This will provide a new view of LRRK neurophysiology in the whole organism, in a way that has not been possible in mouse models.

This project will be co-supervised by Professor Alex Wade from the Department of Psychology.