Abstract
Parkinson’s disease (PD) is characterized by the progressive accumulation of neuronal intracellular aggregates largely composed of alpha-Synuclein (αSyn) protein. The process of αSyn aggregation is induced during aging and enhanced by environmental stresses, such as the exposure to pesticides. Paraquat (PQ) is an herbicide which has been widely used in agriculture and associated with PD. PQ is known to cause an increased oxidative stress in exposed individuals but the consequences of such stress on αSyn conformation remains poorly understood. To study αSyn pathogenic modifications in response to PQ, we exposed Drosophila expressing human αSyn to a chronic PQ protocol. We first showed that PQ exposure and αSyn expression synergistically induced fly mortality. The exposure to PQ was also associated with increased levels of total and phosphorylated forms of αSyn in the Drosophila brain. Interestingly, PQ increased the detection of soluble αSyn in highly denaturating buffer but did not increase αSyn resistance to proteinase K digestion. These results suggest that PQ induces the accumulation of toxic soluble and misfolded forms of αSyn but that these toxic forms do not form fibrils or aggregates that are detected by the proteinase K assay. Collectively, our results demonstrate that Drosophila can be used to study the effect of PQ or other environmental neurotoxins on αSyn driven pathology.
Highlights
Parkinson’s disease (PD) is characterized by the neuronal accumulation of αSynrich cytoplasmic inclusions known as Lewy bodies [1]. αSyn is a vertebrate-specific140 amino-acid presynaptic protein, which can acquire neurotoxic properties during aging and in synucleinopathies such as PD [2]
ΑSyn aggregation is associated with increased αSyn phosphorylation at Ser 129, which has been identified as the predominant pathogenic modification of αSyn present in Lewy bodies in PD and other synucleinopathies [4]
We studied the effect of PQ on αSyn pathogenic modifications using a chronic model of PQ exposure in Drosophila expressing human synuclein alpha (SNCA) gene in neurons
Summary
140 amino-acid presynaptic protein, which can acquire neurotoxic properties during aging and in synucleinopathies such as PD [2]. During this process, soluble αSyn monomers form oligomers that progressively accumulate to produce large αSyn fibrils that constitute the insoluble aggregates [3]. There are multiple factors that can promote or enhance the aggregative process This includes familial missense mutations of αSyn, such as αSynA53T, which are associated with an increased aggregation propensity [9]. Abnormal elevated expression of αSyn promotes its aggregation This is observed in familial duplication or triplication of the synuclein alpha (SNCA) gene, as well as in a risk variant in the non-coding distal element of SNCA, which all lead to a constitutive increased αSyn expression [3,10]
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