[ using juvenile Drosophila melanogaster (fruit fly)] Knocking-out (deactivating) the parkin gene in Drosophila influenced energy metabolism, neuronal resting potential, synaptic development, and kinesis. More specifically, ATP (the universal cellular energy currency) synthesis and oxygen consumption were significantly reduced, and elevated levels of reactive oxygen species were observed. These physiological and metabolic changes suggest that mutations in parkin results in a neuronal energy deficit which underpins bradykinesia.

Current concepts on the development and pathogenesis of Parkinson’s disease focus heavily on the involvement of oxidative stress in inducing cell death in the substantia nigra. Although experimental evidence exists to demonstrate the vulnerability of dopamine neurons to damage by reactive oxygen species, it has remained unclear as to whether the oxidative stress is a consequence of the disease or initially causes the disease. To definitively elucidate the role of oxidative stress in causing the neurophysiological defects observed by mutating the parkin gene, the parkin mutants were initially treated with ‘reactive oxygen species scavengers’, antioxidants which either donate an electron or remove an electron from the reactive species to neutralise their effects on the cell. Surprisingly, introducing scavengers did not restore the resting membrane potential of the neurons or affect the locomotor defects of the mutant juvenile Drosophila, thus suggesting that these defects derive from causes other than oxidative damage.

The wild-type parkin gene was then exploited as a ‘transgene’, and was over-expressed in a parkin mutant to confirm the energetic cause for bradykinesia. Introduction of the wild-type gene entirely restored wild-type functionality. The finding conclusively demonstrates that oxidative stress occurs downstream in the pathology of Parkinson’s disease and cannot therefore be the underlying cause, but simply a product of the neurodegenerative process...

... This demonstration, and the conclusion that metabolic impairment of neurons rather than oxidative stress induces the neuronal damage leading to locomotor disorders, marks a considerable benchmark in our understanding of Parkinson’s disease ...
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