Why did you study the effect of paraquat on the development of Parkinson’s disease in Drosophila?
Paraquat is an herbicide whose exposure is known to increase the risk of developing Parkinson disease. Its use has been prohibited since 2007 in the European Union. The aim of this study was to look at the effects of paraquat on two models of fruit flies genetically modified to express different forms of human α-synuclein. The accumulation and aggregation of α-synuclein in the brain are indeed markers of the progression of Parkinson’s disease. It is primarily an age-related disease, but environmental factors are also suspected in its development. We wanted to know if paraquat by itself caused changes in the protein α-synuclein in these transgenic fruit flies. If so, it would allow for additional models to assess possible links between environmental contaminants and Parkinson’s disease.
How was the study?
The study was carried out on transgenic fruit flies, carriers either of the normal gene for human α-synuclein, or of a mutated gene (A53T), linked to genetic cases of Parkinson’s disease. These cases begin on average around the age of 45 and their progression is rapid and often associated with dementia. Both lines of flies are commonly used to study the molecular and cellular mechanisms that are linked to Parkinson’s disease. We exposed the insects to the herbicide, at a low concentration and for a long time, corresponding to the time required for half of the fruit flies to die.
What are your results?
First, we confirmed that the transgenic fruit flies were more sensitive to paraquat : Drosophila carrying the normal human α-synuclein gene had a reduced lifespan compared to non-transgenic Drosophila and this duration was even shorter for Drosophila carrying the A53T mutation. Next, we showed that the herbicide resulted in an accumulation of toxic and abnormally shaped α-synucleins. These abnormalities are the same as those observed during aging of these insects and are comparable to the effects of Parkinson’s disease in humans. However, another marker of Parkinson’s disease, also observed during the aging of insects, is not not present under the effect of paraquat : this is the strong aggregation of α-synuclein proteins between them.
How can this difference in effects be explained?
The difference in effects raises questions regarding their cause. In the case of paraquat exposure, the accumulation of non-highly aggregated proteins might recall the early stages of Parkinson’s disease. It is therefore possible that with fruit flies exposed to paraquat we observe the beginning of the accumulation process toxic forms of α-synuclein. However, it is also possible that the mechanism of dysregulation induced by the herbicide is not the same as that which is observed during aging. In this hypothesis, exposure to paraquat would not cause a simple acceleration of the disease but it would be at the origin of a other process of accumulation of toxic forms of α-synuclein. To answer the question, it would be necessary to carry out more in-depth studies, in particular to study the cellular mechanisms involved.
What are your conclusions ?
We have shown that Drosophila is a interesting pattern, which can be used to assess the effect of environmental contaminants other than paraquat. Drosophila offers an intermediate model between cell culture and rodents. It’s an animal easy to understand because of its short life, while possessing a complex nervous system. Experiments with these insects are less of an ethical issue than work carried out on rats or mice in the context of regulatory assessments of substances and phytosanitary products.
