Analysis of parkin/pink1 functional pathway in a Drosophila model of Parkinsondisease. (360G-Wellcome-081987_Z_07_Z)

Parkinson s disease (PD) is a common neurodegenerative disorder caused by the progressive loss of dopaminergic neurons, however, the pathologic causes remain unclear. Recently, mitochondrial dysfunction has again received much attention with the findings that the PD-linked genes parkin and pink1 may act in a common pathway to maintain mitochondrial integrity. Drosophila models for mutations in parkin and pink1 recapitulate many features of PD and have become leading model systems with which to s tudy the molecular and genetic mechanisms of PD. Here we propose to use the Drosophila parkin and pink1 models to elucidate the functional pathway in which they act. We shall employ proteomic techniques to identify novel targets of pink1 activity in vivo by isolating endogenous binding partners. We shall also test whether pink1 regulates the activity of parkin by molecular interaction or by an indirect mechanism. In addition, we shall also determine whether parkin and/or pink1 play a role in mit ochondrial fission or fusion events by testing for molecular and genetic interactions with known fission/fusion factors. We also propose to use unbiased genetic screens to uncover other factors in the parkin/pink1 functional pathway.