Pink1 and parkin demonstrate multifaceted roles when co-expressed with Foxo

Abstract

Pink1 has been linked to both autosomal reces- sive and sporadic forms of Parkinson disease. The Pink1 protein is thought to be involved in mitochondrial protection by interacting with parkin to prevent oxidative damage, maintain mitochondrial integrity and regulate mitophagy. Pink1 and parkin have been linked to compo- nents of the insulin receptor (INR) pathway, in- cluding PTEN, Akt and Foxo, but their effects in the INR pathway have been largely overlooked. To further investigate the roles of Pink1/parkin, we have performed co-expression studies to de- termine the effects Pink1 and parkin on the Foxo-induced phenotype of developmental de- fects in the Drosophila eye. We examined di- rected expression of Pink1, parkin, Pink1 or parkin mutants, and Pink1 or parkin interfering RNAs (RNAi) with the overexpression of Foxo in the developing eye of Drosophila. Our findings show that reduction of Pink1 suppresses the effects of Foxo overexpression, where co-overex- pression with Pink1 or parkin increases the se- verity of the phenotype. This suggests that Pink1 and parkin are able to increase the pro- apoptotic effects of Foxo. Contrary to the view that Pink1 and parkin act exclusively as protec- tive proteins in the cell, it is likely that the Pink1/parkin pathway is involved in aspects of cell fate decisions other than degrading toxic proteins and maintaining mitochondrial integ- rity.