α-Synuclein Toxicity in Drosophila melanogaster Is Enhanced by the Presence of Iron: Implications for Parkinson's Disease

Parkinson's disease (PD) is the second most common neurodegenerative disorder, characterized by the preferential loss of dopaminergic neurons and by the accumulation of intracellular inclusions mainly composed of alpha-synuclein (alpha-Syn). While the etiopathogenesis of the disorder is still elusive, recent experimental evidence supports the involvement of ferroptosis, an iron-dependent cell death pathway, in the pathogenesis of PD. In the present work, using different ferroptosis inducers and inhibitors, we evaluated, in vivo, the involvement of iron in the alpha-Syn-mediated toxicity. Using a Drosophila melanogaster model of PD based on the selective over-expression of alpha-Syn within dopaminergic neurons, we demonstrated that the over-expression of alpha-Syn promotes the accumulation of protein aggregates, which is accompanied by dopaminergic neurodegeneration, locomotor impairment, and lifespan reduction. These pathological phenotypes were further exacerbated by reduced intracellular levels of glutathione or increased concentrations of iron. Coherently, both the use of an iron chelator and the presence of the antioxidant compound N-acetylcysteine exerted protective effects. Overall, our results support the involvement of ferroptosis in the alpha-Syn-mediated toxicity.

Automated summary

Parkinson's disease (PD) is the second most common neurodegenerative disorder characterized by the loss of dopaminergic neurons and accumulation of alpha-synuclein. Recent evidence suggests the involvement of iron-dependent cell death pathway, ferroptosis, in the pathogenesis of PD. This study using a Drosophila melanogaster model of PD demonstrated that over-expression of alpha-synuclein leads to protein aggregate accumulation and dopaminergic neurodegeneration, which are worsened by decreased glutathione levels or increased iron concentrations.