Α-Synuclein E46K Mutation and Involvement of Oxidative Stress in a Drosophila Model of Parkinson's Disease. (5th July 2021)

• Record Type: Journal Article
• Authors: Reiszadeh Jahromi, Samaneh; Ramesh, S. R.; Finkelstein, David I.; Haddadi, Mohammad
• Other Names: Teive Hélio Academic Editor.
• Is Part Of: Parkinson's disease. Volume 2021(2021)
• Publication Date: 2021-07-05
• Subjects: Parkinson's disease -- Periodicals; Parkinson's disease -- Treatment -- Periodicals; 616.833005
• DOI: 10.1155/2021/6621507
• Languages: English
• ISSNs: 2090-8083

Abstract

Abstract : Parkinson's disease (PD) is an age-associated neurodegenerative condition in which some genetic variants are known to increase disease susceptibility on interaction with environmental factors inducing oxidative stress. Different mutations in the SNCA gene are reported as the major genetic contributors to PD. E46K mutation pathogenicity has not been investigated as intensive as other SNCA gene mutations including A30P and A53T . In this study, based on the GAL4-UAS binary genetic tool, transgenic Drosophila melanogaster flies expressing wild-type and E46K-mutated copies of the human SNCA gene were constructed. Western blotting, immunohistochemical analysis, and light and confocal microscopy of flies' brains were undertaken along with the survival rate measurement, locomotor function assay, and ethanol and paraquat (PQ) tolerance to study α -synuclein neurotoxicity. Biochemical bioassays were carried out to investigate the activity of antioxidant enzymes and alterations in levels of oxidative markers following damages induced by human α -synuclein to the neurons of the transgenic flies. Overexpression of human α -synuclein in the central nervous system of these transgenic flies led to disorganized ommatidia structures and loss of dopaminergic neurons. E46K α -synuclein caused remarkable climbing defects, reduced survivorship, higher ethanol sensitivity, and increased PQ-mediated mortality. A noticeable decline in activity of catalase and superoxide dismutase enzymes besides considerable increase in the levels of lipid peroxidation and reactive oxygen species was observed in head capsule homogenates of α -synuclein-expressing flies, which indicates obvious involvement of oxidative stress as a causal factor in SNCA E46K neurotoxicity. In all the investigations, E46K copy of the SNCA gene was found to impose more severe defects when compared to wild-type SNCA . It can be concluded that the constructed Drosophila models developed PD-like symptoms that facilitate comparative studies of molecular and cellular pathways implicated in the pathogenicity of different α -synuclein mutations.