<i>Pink1 </i>and <i>parkin</i> demonstrate multifaceted roles when co-expressed with <i>Foxo</i>

Abstract

Pink1 has been linked to both autosomal recessive 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 components of the insulin receptor (INR) pathway, including 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 determine the effects Pink1 and parkin on the Foxo-induced phenotype of developmental defects in the Drosophila eye. We examined directed 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-overexpression with Pink1 or parkin increases the severity of the phenotype. This suggests that Pink1 and parkin are able to increase the proapoptotic effects of Foxo. Contrary to the view that Pink1 and parkin act exclusively as protective 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 integrity.

Drosophila Models of Parkinson Disease

“…Both can lead to abnormal wing positioning ("wing held-up" for loss of parkin and "wings drooped" for loss of Pink1), apparently due to flight muscle degeneration characterized by mitochondrial morphology defects. However, it should be noted that Pink1 and parkin have been demonstrated to increase the pro-apoptotic effects of foxo when expressed in the developing eye (Todd and Staveley, 2013). This study began with a Pink1 overexpression-induced phenotype in the developing eye that was prevented by the loss-of-function of Sir2.…”