Abstract
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.
