Molecular mechanisms of Parkin translocation to mitochondria

Parkinson’s disease (PD) is a devastating, currently incurable brain disorder. In PD, specific nerve cells gradually die, causing tremor, slowness of movement, falls, dementia and many other problems. Why these nerve cells die, is not well understood. However, in rare familial cases PD is caused by genetic mutations that disrupt the function of the protein Parkin. Recently, it was discovered that Parkin is crucial to maintain a healthy pool of mitochondria in the cell. Mitochondria are cellular organelles that are essential for energy production but, when damaged, can induce cell death. Dysfunctional mitochondria must therefore be promptly eliminated if the cell is to survive. When mitochondria are damaged, Parkin rapidly and selectively moves from its usual location in the cell to the sick mitochondria and targets them for destruction, thus protecting the cell. The molecular mechanisms underlying this rapid movement of Parkin to sick mitochondria are currently unknown. In this project we will use state-of-the-art proteomic methods to unravel the molecular machinery that regulates the translocation of Parkin to damaged mitochondria. Using cell culture and fly models of PD we will investigate how specific proteins interact with Parkin to modulate its mitochondrial translocation. This work may identify new molecular targets for disease-modifying therapy in PD.