An underlying cause of Parkinson’s Disease

Copied from The Northwest Parkinson’s Foundation Weekly News Update

 

Oxidative stress is no longer a prime candidate for the development of Parkinson’s disease, suggests a recent study at the University of York Biology department.
Ashley Ferro

Theyourker.co.uk - Parkinson’s disease results from the progressive degeneration of specific neurons in the substantia nigra pars compacta, a region of the midbrain which modulates synaptic activity in the basal ganglion. The complex wiring between regions of the basal ganglion is essential for the regulation of motor activity. Disrupting this interaction through degeneration of the dopamine neurons which modulate this system consequently results in the characteristic motor impairments observed in Parkinson’s patients, predominantly resting tremor, rigidity, and bradykinesia (slow movement). The mechanisms underpinning this neuronal cell death in the substantia nigra have remained highly elusive, and oxidative stress has been a serious contender for this role for quite some time.

Undergraduate biology students at the University of York worked as part of the team to exploit the powerful model system of juvenile Drosophila melanogaster (fruit fly) and an understanding of Mendelian genetics to study the influence of knocking-out the Juvenile Parkinson’s-related gene parkin on neuronal characteristics, metabolism and movement.

The juvenile Drosophila system faithfully models progression of the disease in humans, thus allowing direct and highly translatable study of the neurophysiological defects which lead to locomotor impairment. 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 is the first time the interaction between central nervous system deficits and bradykinesia has been experimentally demonstrated, a relationship which has merely been inferred by previous studies within the field. 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 . Dr Chris Elliott, who led the study, explains the next direction of Parkinson’s research in the deparment, "Our next step will be to test a range of drugs which are known to relieve oxidative stress in cells, to test if they - like the transgenes - don't rescue the parkin locomotion defects." Identification of drugs which can reduce oxidative stress in the neurons responsible for modulating interactions in the basal ganglion may have considerable implications for Parkinson’s treatments in the future. The quality and impact of this research pays tribute to the abilities of the students and academics at the York Biology department.

References Vincent, A., Briggs, L., Chatwin, G., Emery, E., Tomlins, R., Oswald, M., Middleton, A., Evans, G., Sweeney, S. and Elliott, C. (2012) parkin-induced defects in neurophysiology and locomotion are generated by metabolic dysfunction and not oxidative stress. Human Molecular Genetics, 1-10.

http://www.theyorker.co.uk/lifestyle/scienceand%20technology/12300