| Summary: | Parkinson’s Disease (PD) is a neurodegenerative disease, with severely reduced movement in patients. The main effect is the loss of dopaminergic neurons in the central nervous system (CNS). Null mutations of the parkin gene are known to cause PD. I found that Drosophila melanogaster (D. melanogaster) parkin null (dparkin) mutant larvae show neurophysiological abnormalities, a bradykinesia-like locomotory defect and synaptic overgrowth at the neuromuscular junction (NMJ). Neuronal overgrowth is rescued with either muscle or neuronal expression of wild-type dparkin in dparkin mutant larvae. The ubiquitous expression of antioxidant enzymes have varying degrees of rescue dependent on their properties and site of action in dparkin mutant larvae. Manipulating c-jun-N-terminal kinase (JNK) signaling components or JNK interacting detoxification enzymes (Glutathione-s-transferase (GST) or Thioredoxin reductase 2 (TRX-R2)) ameliorated all the types of dparkin mutant larval phenotypes. Superoxide Dismutase 1 (Sod1) expression rescued overgrowth but failed to rescue the neurophysiological defect or the locomotion in dparkin mutant larvae. Additionally, genetically manipulating AMP-activated protein Kinase (AMPK), which is involved in the energy homeostasis, rescued overgrowth and neurophysiological dysfunction but not the locomotory defects. The pharmacological manipulation with dopaminergic drugs, and classical AMPK activators (metformin and 5-Aminoimidazole-4-carboxamide ribonucleotide (AICAR)) or resveratrol failed to rescue dparkin larval phenotypes. I conclude that neuronal, rather than muscle, failure is key to the bradykinesia observed in dparkin mutant larvae. The main defect is suggested to be the depletion of neuronal energy reserve leading to synaptic dysfunction, rather than oxidative stress. Together these observations suggest oxidative stress could be a downstream consequence of a metabolic dysfunction.
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