Reduction of protein translation and activation of autophagy protect against PINK1 pathogenesis in Drosophila melanogaster

Mutations in PINK1 and Parkin cause familial, early onset Parkinson's disease. In Drosophila melanogaster, PINK1 and Parkin mutants show similar phenotypes, such as swollen and dysfunctional mitochondria, muscle degeneration, energy depletion, and dopaminergic (DA) neuron loss. We previously showed that PINK1 and Parkin genetically interact with the mitochondrial fusion/fission pathway, and PINK1 and Parkin were recently proposed to form a mitochondrial quality control system that involves mitophagy. However, the in vivo relationships among PINK1/Parkin function, mitochondrial fission/fusion, and autophagy remain unclear; and other cellular events critical for PINK1 pathogenesis remain to be identified. Here we show that PINK1 genetically interacted with the protein translation pathway. Enhanced translation through S6K activation significantly exacerbated PINK1 mutant phenotypes, whereas reduction of translation showed suppression. Induction of autophagy by Atg1 overexpression also rescued PINK1 mutant phenotypes, even in the presence of activated S6K. Downregulation of translation and activation of autophagy were already manifested in PINK1 mutant, suggesting that they represent compensatory cellular responses to mitochondrial dysfunction caused by PINK1 inactivation, presumably serving to conserve energy. Interestingly, the enhanced PINK1 mutant phenotype in the presence of activated S6K could be fully rescued by Parkin, apparently in an autophagy-independent manner. Our results reveal complex cellular responses to PINK1 inactivation and suggest novel therapeutic strategies through manipulation of the compensatory responses.
Author Summary Parkinson's disease is the most common neurodegenerative disease affecting the aging population. Clinically it manifests as tremor, muscle rigidity, slow movement, and postural instability. Parkinson's disease is a chronic disorder, and its occurrence and progression are determined by genetic backgrounds and environmental factors. Although the most common forms of Parkinson's disease, the so-called “idiopathic” forms, generally affect people older than 50, some familial forms of the disease occur before age 40. Mutations in PINK1 and Parkin genes have been associated with the latter forms of Parkinson's disease. The inactivation of PINK1 or Parkin causes dysfunction of mitochondria, the powerhouse of the cell, leading to the degeneration of tissues such as the brain and muscle that have high energy demand. In an effort to understand how genetic mutations in PINK1 result in disease and to find effective ways to intervene, we have performed genetic studies in the model organism Drosophila melanogaster and found that reduced protein translation or increased autophagy can efficiently mitigate the phenotypes caused by PINK1 inactivation. Our result suggests that pharmacological manipulations of these newly identified PINK1-interacting pathways may prove beneficial for the treatment of Parkinson's disease.