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

Abstract

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 α-synuclein (α-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 α-Syn-mediated toxicity. Using a Drosophila melanogaster model of PD based on the selective over-expression of α-Syn within dopaminergic neurons, we demonstrated that the over-expression of α-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 α-Syn-mediated toxicity.

HDAC2 counteracts vascular calcification by activating autophagy in chronic kidney disease

“…In addition, AMPK/mTOR is a critical hub to promote autophagy. 34,35 Previous studies suggest that activating AMPK/mTOR pathway enhances the autophagic process, which results the reduction of VSMC osteogenic differentiation in vascular calcification both in vivo and in vitro. [36][37][38] Considering that HDAC2 has been demonstrated to increase AMPK activity, 39 we thought that AMPK/mTOR pathway might be a potential mechanism in autophagy activation regulated by HDAC2.…”

“…Taken together, autophagic activation might be an underlying mechanism by HDAC2 on the inhibition of vascular calcification. In addition, AMPK/mTOR is a critical hub to promote autophagy 34,35 . Previous studies suggest that activating AMPK/mTOR pathway enhances the autophagic process, which results in the reduction of VSMC osteogenic differentiation in vascular calcification both in vivo and in vitro 36–38 .…”

Oxidative Stress and Neuroinflammation in Parkinson’s Disease: The Role of Dopamine Oxidation Products

“…In this context, many mechanisms have been proposed, including the presence of highly branched, poorly myelinated long axons, which are associated with mitochondrial oxidative stress, and large fluctuations in cytosolic calcium levels [ 101 ]. Another interesting process that has recently emerged in the literature is ferroptosis, an iron-dependent cell death pathway that involves the accumulation of lipid peroxidation accompanied by the concomitant depletion of intracellular GSH and that has been suggested as a contributing mechanism of neuronal death in PD [ 102 , 103 , 104 ]. This process is regulated in a complex way through the involvement of multiple enzymes, iron-binding proteins, and several transport systems.…”

Ferroptosis Induced by Pollutants: An Emerging Mechanism in Environmental Toxicology

“…62 The findings from Hu et al revealed that ferroptosis is a prominent toxicity mechanism in Cd-induced adverse outcomes in Drosophila melanogaster, leading to growth retardation in larvae and altered behaviors, including decreased activity and increased sleep duration in females. 63 Given the involvement of ferroptosis in neurodegenerative disorders in Drosophila melanogaster, 64,65 Cdinduced behavioral disturbances likely arise from nervous system abnormalities.…”