Drosophila as a model for exploring the effects of pesticides on Parkinson’s disease
The Drosophila melanogaster or fruit fly may be used to assess whether pesticides induce an increased risk of developing Parkinson’s disease. This was the conclusion reached by scientists in the ANSES Lyon Laboratory’s Neurodegenerative Diseases Unit, who have been collaborating with researchers from the École Normale Supérieure in Lyon. Working on paraquat, they also showed that the effects of this compound on proteins were not strictly identical to those of ageing. We interviewed Jean-Noël Arsac, one of the authors of the study.
Why did you study the effect of paraquat on the development of Parkinson’s disease in Drosophila?
Exposure to the herbicide paraquat is known to increase the risk of developing Parkinson's disease. Paraquat has been banned in the European Union since 2007. This study aimed to investigate the effects of paraquat on two Drosophila models genetically modified to express different forms of human α-synuclein. The accumulation and aggregation of α-synuclein in the brain are markers of the progression of Parkinson’s disease. This is mainly an age-related disease, but environmental factors are also suspected to be involved in its development. We wanted to find out whether paraquat by itself caused changes in α-synuclein proteins in transgenic Drosophila. If this were true, it would provide additional models for assessing potential links between environmental contaminants and Parkinson’s disease.
What was the study process?
The study was conducted on transgenic Drosophila carrying either the normal human α-synuclein gene or a mutated gene (A53T) linked to genetic cases of Parkinson’s disease. Such cases begin on average around the age of 45 and progress rapidly, often in association with dementia. Both fly strains are typically used to study molecular and cellular mechanisms associated with Parkinson’s disease. We exposed the insects to the herbicide at low concentrations over the time required for half of the Drosophila to die.
What results did you get?
We first confirmed that transgenic Drosophila were more sensitive to paraquat: Drosophila carrying the normal human α-synuclein gene had a reduced lifespan compared to non-transgenic Drosophila, and this was even shorter for Drosophila carrying the A53T mutation. We then showed that the herbicide caused an accumulation of toxic α-synuclein with an abnormal conformation. This accumulation of abnormal α-synuclein is also observed in ageing insects and is similar to the effects of Parkinson’s disease in humans. However, the aggregation of α-synuclein, another marker of the disease also observed in ageing insects, was not found to be an effect of paraquat.
What causes this difference in effects?
These different effects raise the question of their causes. In the case of paraquat exposure, the accumulation of proteins that are not highly aggregated may be reminiscent of the early stages of Parkinson’s disease. It is therefore possible that in Drosophila exposed to paraquat, we are seeing the beginning of the accumulation process of toxic forms of α-synuclein. However, it is also possible that the mechanism of disruption induced by the herbicide is not the same as that observed during ageing. In this hypothesis, instead of simply accelerating the disease, paraquat exposure would also induce another process of accumulation of toxic forms of α-synuclein. To answer this question, more detailed studies are needed, in particular to investigate the cellular mechanisms involved.
What conclusions did you draw?
We have shown that Drosophila provide a valuable model that may be used to assess the effects of other environmental contaminants besides paraquat. Drosophila provide an intermediate model between cell culture and the use of rodents. Because of its short life span, the fruit fly is easy to understand, but its nervous system is nevertheless complex. Experiments with these insects pose less of an ethical challenge than working with rats or mice in the context of regulatory assessments of plant protection compounds and products.