parkin induced defects in neurophysiology and locomotion are generated by metabolic dysfunction and not oxidative stress

Abstract

Parkinson's disease (PD) is characterised by movement disorders, including bradykinesia. Analysis of inherited, juvenile PD, identified several genes linked via a common pathway to mitochondrial dysfunction. In this study we demonstrate that the larva of the Drosophila parkin mutant faithfully models the locomotory and metabolic defects of PD and is an excellent system for investigating their interrelationship. parkin larvae displayed a marked bradykinesia that was caused by a reduction in both the frequency of peristalsis and speed of muscle contractions. Rescue experiments confirmed that this phenotype was due to a defect in the nervous system and not the muscle. Furthermore, recordings of motoneuron activity in parkin larvae revealed reduced bursting and a striking reduction in evoked and miniature excitatory junction potentials, suggesting a neuronal deficit. This was supported by our observations in parkin larvae that the resting potential was depolarised, oxygen consumption and ATP concentration were drastically reduced while lactate was increased. These findings suggest neuronal mitochondrial respiration is severely compromised and there is a compensatory switch to glycolysis for energy production.parkin mutants also possessed overgrown neuromuscular synapses, indicative of oxidative stress, that could be rescued by overexpression of parkin or scavengers of reactive oxygen species. Surprisingly, scavengers of reactive oxygen species did not rescue the resting membrane potential and locomotory phenotypes. We therefore propose that mitochondrial dysfunction in parkin mutants induces Parkinsonian bradykinesia via a neuronal energy deficit and resulting synaptic failure, rather than as a consequence of downstream oxidative stress.