<i>SNCA</i> ^<i>E46K</i> transgenic <i>Drosophila</i> Model of Parkinson’s Disease Confirmed the Causative Role of Oxidative Stress

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Parkinson’s disease (PD) is a class of neurodegenerative disorders in which, complex interactions of genetic and environmental agents are involved in the etiology of both sporadic and familial PD cases. α-synuclein-encoding SNCA gene is known as one of the major genetic contributors of this disease. E46K mutation in SNCA gene has not been investigated as intensive as other SNCA gene mutations including A30P and A53T. In this study, to induce PD in Drosophila flies, UAS-hSNCA WT and UAS-hSNCA E46K transgenic fly lines were constructed, where SNCA gene was over-expressed in flies brains using GAL4-UAS genetic system. Western blot analysis of head samples of SNCA -expressing flies verified SNCA expression at protein level. Light and electron microscopy analysis of ommatidial structures were performed to verify neurodegeneration as a result of α-synuclein gene overexpression in Drosophila transgenic flies. Confocal microscopy analysis of dopaminergic neuron clusters verified cell loss following SNCA E46K expression in the flies’ brain. E46K α-synuclein gene over-expression resulted in an evident decline in longevity as well as climbing ability of the flies. Biochemical studies of transgenic flies showed a remarkable decline in antioxidant enzymes activity and a significant increase in oxidative markers level as well as AchE enzyme activity. Oxidative stress has been known as a causal factor in PD pathogenesis, following expression of E46K mutant version of human SNCA gene. This Drosophila model is able to facilitate comparative studies of both molecular and cellular assays implicated in the assessment of neurotoxicity of different α-synuclein mutations.

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