SNCAE46K transgenic Drosophila Model of Parkinson’s Disease Confirmed the Causative Role of Oxidative Stress (original) (raw)
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Parkinson's Disease
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 oxi...
ACS chemical neuroscience, 2018
α-Synuclein (α-Syn) aggregation and amyloid formation are associated with loss of dopaminergic neurons in Parkinson's disease (PD). In addition, familial mutations in α-Syn are shown to be one of the definite causes of PD. Here we have extensively studied familial PD associated α-Syn G51D, H50Q and E46K mutations using Drosophila model system. Our data showed that flies expressing α-Syn familial mutants have a shorter lifespan and exhibit more climbing defects compared to wild-type (WT) flies in an age-dependent manner. The immuno-fluorescence studies of the brain from the old flies showed more dopaminergic neuronal cell death in all mutants compared to WT. This adverse effect of α-Syn familial mutations highly correlated with the sustained population of oligomer production/ retention in mutant flies. Furthermore, this was supported by our in vitro studies, where significantly higher amount of oligomer was observed in mutants compared to WT. The data suggest that the sustained p...
Fly, 2024
Parkinson's disease (PD), the most prevalent type of parkinsonism, is a progressive neurodegenerative condition marked by several non-motor and motor symptoms. PD is thought to have a complex aetiology that includes a combination of age, genetic predisposition, and environmental factors. Increased expression of α-synuclein (α-Syn) protein is central to the evolvement of neuropathology in this devastating disorder, but the potential of ribose-cysteine and levodopa in abating pathophysiologic changes in PD model is unknown. Crosses were set up between flies conditionally expressing a pathological variant of human α-Syn (UAS-α-Syn) and those expressing GAL4 in neurons (elav-GAL4) to generate offspring referred to as PD flies. Flies were randomly assigned to five groups (n = 40) from the total population of flies, with each group having five replicates. Groups of PD flies were treated with either 500 mg/kg ribose-cysteine diet, 250 mg/kg levodopa diet, or a combination of the two compounds for 21 days, whereas the control group (w 1118) and the PD group were exposed to a diet without ribose-cysteine or levodopa. In addition to various biochemical and neurochemical assays, longevity, larval motility, and gravitaxis assays were carried out. Locomotive capability, lifespan, fecundity, antioxidant state, and neurotransmitter systems were all significantly (p < 0.05) compromised by overexpression of α-Syn. However, flies treated both ribose cysteine and levodopa showed an overall marked improvement in motor functions, lifespan, fecundity, antioxidant status, and neurotransmitter system functions. In conclusion, ribose-cysteine and levodopa, both singly and in combination, potentiated a therapeutic effect on alpha-synuclein transgenic Drosophila melanogaster models of Parkinsonism.
Parkinson’s Disease: Insights from Drosophila Model
2018
Parkinson’s disease (PD) is a medical condition that has been known since ancient times. It is the second most common neurodegenerative disorder affecting approximately 1% of the population over 50 years. It is characterized by both motor and non-motor symptoms. Most of PD cases are sporadic while 5–10% cases are familial. Environment factors such as exposure to pesticides, herbicides and other heavy metals are expected to be the main cause of sporadic form of the disease. Mutation of the susceptible genes such as SNCA, PINK1, PARKIN, DJ1, and others are considered to be the main cause of the familial form of disease. Drosophila offers many advantages for studying human neurodegenerative diseases and their underlying molecular and cellular pathology. Shorter life span; large number of progeny; conserved molecular mechanism(s) among fly, mice and human; availability of many techniques, and tools to manipulate gene expression makes drosophila a potential model system to understand the...
The Journal of Neuroscience, 2008
␣-Synuclein aggregates are a common feature of sporadic Parkinson's disease (PD), and mutations that increase ␣-synuclein abundance confer rare heritable forms of PD. Although these findings suggest that ␣-synuclein plays a central role in the pathogenesis of this disorder, little is known of the mechanism by which ␣-synuclein promotes neuron loss or the factors that regulate ␣-synuclein toxicity. To address these matters, we tested candidate modifiers of ␣-synuclein toxicity using a Drosophila model of PD. In the current work, we focused on phase II detoxification enzymes involved in glutathione metabolism. We find that the neuronal death accompanying ␣-synuclein expression in Drosophila is enhanced by loss-of-function mutations in genes that promote glutathione synthesis and glutathione conjugation. This neuronal loss can be overcome by genetic or pharmacological interventions that increase glutathione synthesis or glutathione conjugation activity. Moreover, these same pharmacological agents suppress neuron loss in Drosophila parkin mutants, a loss-of-function model of PD. Our results suggest that oxidative stress is a feature of ␣-synuclein toxicity and that induction of the phase II detoxification pathway represents a potential preventative therapy for PD.
Gene expression changes presage neurodegeneration in a Drosophila model of Parkinson's disease
Human Molecular Genetics, 2003
Transgenic Drosophila expressing human a-synuclein faithfully replicate essential features of human Parkinson's disease, including age-dependent loss of dopaminergic neurons, Lewy-body-like inclusions and locomotor impairment. To define the transcriptional program encoding molecular machinery involved in asynuclein pathology, we characterized expression of the entire Drosophila genome at pre-symptomatic, early and advanced disease stages. Fifty-one signature transcripts, including lipid, energy and membrane transport mRNAs, were tightly associated with a-synuclein expression. Most importantly, at the presymptomatic stage, when the potential for neuroprotection is greatest, expression changes revealed specific pathology. In age-matched tau transgenic Drosophila, the transcription of a-synuclein associated genes was normal, suggesting highly distinct pathways of neurodegeneration. Temporal profiling of progressive gene expression changes in neurodegenerative disease models provides unbiased starting points for defining disease mechanisms and for identifying potential targets for neuroprotective drugs at pre-clinical stages.
Journal of Neuroscience, 2008
␣-Synuclein aggregates are a common feature of sporadic Parkinson's disease (PD), and mutations that increase ␣-synuclein abundance confer rare heritable forms of PD. Although these findings suggest that ␣-synuclein plays a central role in the pathogenesis of this disorder, little is known of the mechanism by which ␣-synuclein promotes neuron loss or the factors that regulate ␣-synuclein toxicity. To address these matters, we tested candidate modifiers of ␣-synuclein toxicity using a Drosophila model of PD. In the current work, we focused on phase II detoxification enzymes involved in glutathione metabolism. We find that the neuronal death accompanying ␣-synuclein expression in Drosophila is enhanced by loss-of-function mutations in genes that promote glutathione synthesis and glutathione conjugation. This neuronal loss can be overcome by genetic or pharmacological interventions that increase glutathione synthesis or glutathione conjugation activity. Moreover, these same pharmacological agents suppress neuron loss in Drosophila parkin mutants, a loss-of-function model of PD. Our results suggest that oxidative stress is a feature of ␣-synuclein toxicity and that induction of the phase II detoxification pathway represents a potential preventative therapy for PD.
Parkinson's Disease, 2011
Parkinson's disease (PD) is the second most common neurodegenerative disorder and is mainly characterized by the selective and progressive loss of dopaminergic neurons, accompanied by locomotor defects. Although most PD cases are sporadic, several genes are associated with rare familial forms of the disease. Analyses of their function have provided important insights into the disease process, demonstrating that three types of cellular defects are mainly involved in the formation and/or progression of PD: abnormal protein aggregation, oxidative damage, and mitochondrial dysfunction. These studies have been mainly performed in PD models created in mice, fruit flies, and worms. Among them, Drosophila has emerged as a very valuable model organism in the study of either toxin-induced or genetically linked PD. Indeed, many of the existing fly PD models exhibit key features of the disease and have been instrumental to discover pathways relevant for PD pathogenesis, which could facilitate the development of therapeutic strategies.
Challenges in Parkinson's Disease, 2016
Parkinson's disease (PD) is the second most common neurodegenerative disorder affecting approximately 1% of the population over age 50. PD is widely accepted as a multifactorial disease with both genetic and environmental contributions. Despite extensive research conducted in the area the precise etiological factors responsible remain elusive. In about 95% Parkinsonism is considered to have a sporadic component. There are currently no established curative, preventative, or diseasemodifying interventions, stemming from a poor understanding of the molecular mechanisms of pathogenesis. Here lies the importance of animal models. Pharmacological insults cause Parkinsonian like phenotypes in Drosophila, thereby modelling sporadic PD. The pesticides paraquat and rotenone induced oxidative damage causing cluster specific DA neuron loss together with motor deficits. Studies in fly PD model have deciphered that signaling pathways such as phosphatidylinositol 3kinase (PI3K/Akt and target of rapamycin (TOR), c-Jun N-terminal kinase (JNK) have been defective. Further, these studies have demonstrated that fruit fly can be a potential model to screen chemical compounds for their neuroprotective efficacy. This chapter overviews current knowledge on the pathophysiology of sporadic PD employing Drosophila model and discusses the future perspectives. Further we emphasize the importance of performing genome wide screens in fly model, which
Integrative Medicine Research, 2017
Background: Oxidative stress is one of the key components of the pathology of various neurodegenerative disorders. Parkinson's disease (PD) is characterized by the progressive loss of dopaminergic neurons owing to the aggregation of alpha-synuclein (␣S) in the brain. A number of polyphenols have been reported to inhibit the ␣S aggregation resulting in the possible prevention of PD. The involvement of free radicals in mediating the neuronal death in PD has also been implicated. Methods: In the present study, the transgenic flies expressing human ␣S in the brain were exposed to 10 M, 20 M, 40 M, and 80 M of apigenin established in diet for 24 days. Results: The flies showed an increase in life span, glutathione, and dopamine content. The exposure of PD flies to various doses of apigenin also results in the reduction of glutathione-S-transferase activity, lipid peroxidation, monoamine oxidase, caspase-3, and caspase-9 activity in a dose-dependent manner. Conclusion: The results of the present study reveal that apigenin is potent in increasing the life span, dopamine content, reduced the oxidative stress as well as apoptosis in transgenic Drosophila model of PD.