Suppression of neurodegeneration in the Drosophila models of human neurodegenerative disorders
Casino, Brittany A.
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Background: Leigh Syndrome (LS) is the most common mitochondrial disorder affecting infants and children. There is currently no cure or effective treatment, with the disease almost always being fatal. Our lab has previously identified a mutation ( levy ) that provides a model of LS in Drosophila melanogaster . Our lab has now identified Su(levy) , which suppresses levy induced neurodegeneration(ND). The Su(levy) mutation reduces loss of neurons in levy flies, and makes them resistant to temperature-induced-paralysis, a phenotypic marker of LS in Drosophila . The Su(levy) mutation has been localized to an area of eight genes on the second chromosome using recombination and deficiency mapping. Previous data have suggested that the drosha gene is currently the most likely candidate to be the suppressor. The cause of ND in levy might be reactive oxygen species (ROS) induced oxidative stress, a feature common to many neurodegenerative disorders such as Parkinson's Disease (PD) and Alzheimer's Disease (AD), broadening the suppressor mutation's application to possibly include PD and AD. Methods: Paralysis testing was done in a 38°C water bath, with paralysis time characterized by when the fly took its last step or the larvae became stationary. Sub-lethal doses of rotenone were fed to wild-type and suppressor flies to determine whether the suppressor mutation would rescue flies from locomotor deficits induced by the pesticide. A melatonin and water mixture was used to rehydrate Drosophila instant medium for exposure of flies to the antioxidant. Results: The Su(levy) mutation made the levy flies resistant to paralysis. On the other hand, other experiments have shown that the Su(levy) mutation protects flies from the effect of the rotenone on locomotion and longevity. Preliminary sequencing has identified three point mutations within the drosha gene that are candidates for the suppressor mutation. Discussion: The suppressor mutation itself is not detrimental in a heterozygous state, while lethal in a homozygous state. Since oxidative stress might be the cause of ND in the levy mutant, we are expanding the scope of our studies on the suppressor mutation to involve other neurodegenerative diseases, such as PD and AD. Suppressor's effects will be measured through longevity, locomotor, and measurement of oxidative stress through ROS assays. Su(levy) may be playing a role in protection from rotenone induced toxicity. Our lab is currently working on identifying the suppressor gene, along with testing whether it will suppress the neurodegeneration in the Drosophila models of AD and PD. If it is found that our suppressor can alleviate neurodegeneration in LS, AD, and PD, this could to lead to therapies for multiple neurodegenerative disorders.