Abstract
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.
Highlights
Parkinson’s disease (PD) is the most common neurodegenerative disease affecting movement and currently there is no cure
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
Summary
Parkinson’s disease (PD) is the most common neurodegenerative disease affecting movement and currently there is no cure. Increasing evidences suggest that mitochondrial dysfunction may be linked to the pathogenesis of both sporadic and familial forms of PD. Recent genetic studies of rare familial forms of PD identified multiple disease genes, including PINK1 and Parkin [1,2]. The inactivation of Drosophila orthologs of PINK1 or Parkin resulted in similar phenotypes, with the formation of enlarged, swollen mitochondria preceding muscle degeneration, DA neuron loss and spermatogenesis failure [5,6,7]. Further analysis showed that overexpression (OE) of Parkin could rescue PINK1 mutant phenotype, but not vice versa, suggesting that PINK1 and Parkin may function in the same pathway, with Parkin acting downstream of PINK1 [5,6,7]. Promoting mitochondrial fission by either overexpression of mitochondrial fission protein Drp or downregulation of mitochondrial fusion proteins Marf (the D. melanogaster homolog of mammalian mitofusin) or Opa could completely rescue PINK1 or Parkin mutant phenotypes, suggesting that PINK1 and Parkin might regulate mitochondrial dynamics by interacting with the mitochondrial fusion/fission machinery [8,9,10]
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