Synergism of IP3R and Parkin mutants identifies mitochondrial stress as an early feature of Parkinson's disease

Our understanding of mechanisms underlying familial Parkinson's disease (PD) have benefitted from studies in Drosophila models of PD. However, in a majority of patients with PD, the disease occurs sporadically, and cellular phenotypes that arise early in sporadic PD are not yet fully understood. A genetic predisposition, arising from variants in pathways that impact dopaminergic neuron health could be one cause of sporadic PD. Here, we studied Drosophila with single-copy mutation of the recessive IP3R-encoding gene (itpr) in combination with a recessive null mutation of the parkin gene. Whereas individual mutants appeared normal, in combination, the genes synergised so that flies exhibited flight motor deficits with a focus in a subset of central dopaminergic neurons. Surprisingly, mitophagy and mitochondrial Ca2+ were barely affected. Instead, flight motor deficits correlated with elevated levels of mitochondrial H2O2, and reducing H2O2 levels by genetic means restored mitochondrial function and flight to a significant extent. This study underlines the importance of mitochondrial oxidative stress as an early phenotype in PD and suggests that humans with recessive variants in either pathway have a higher chance of developing sporadic PD.