Superoxide dismutating molecules rescue the toxic effects of PINK1 and parkin loss

Abstract

Reactive oxygen species exert important functions in regulating several cellular signalling pathways. However, an excessive accumulation of reactive oxygen species can perturb the redox homeostasis leading to oxidative stress, a condition which has been associated to many neurodegenerative disorders. Accordingly, alterations in the redox state of cells and mitochondrial homeostasis are established hallmarks in both familial and sporadic Parkinson’s disease cases. PINK1 and Parkin are two genes which account for a large fraction of autosomal recessive early-onset forms of Parkinson’s disease and are now firmly associated to both mitochondria and redox homeostasis. In this study we explored the hypothesis that superoxide anions participate in the generation of the Parkin and PINK1 associated phenotypic effect by testing the capacity of endogenous and exogenous superoxide dismutating molecules to rescue the toxic effects induced by loss of PINK1 or Parkin, in both cellular and fly models. Our results demonstrate the positive effect of an increased level of superoxide dismutase proteins on the pathological phenotypes, both in vitro and in vivo. A more pronounced effectiveness for mitochondrial SOD2 activity points to the superoxide radicals generated in the mitochondrial matrix as the prime suspect in the definition of the observed phenotypes. Moreover, we also demonstrate the efficacy of a SOD-mimetic compound, M40403, to partially ameliorate PINK1/Parkin phenotypes in vitro and in vivo. These results support the further exploration of SOD-mimetic compounds as a therapeutic strategy against Parkinson’s disease.

Oxidative stress in the aging substantia nigra and the etiology of Parkinson's disease

“…An abundance of evidence from genetic and toxin‐induced animal models of PD demonstrates redox imbalance contributes to SNc neurodegeneration, and further, that restoring redox homeostasis with these neurons protects against degeneration (Biosa et al, ; Devos et al, ; Dias et al, ; Filograna, Beltramini, Bubacco, & Bisaglia, ; Zhou & Freed, ). These data, however, are made possible by our ability to carefully dissect and assay brain tissue from these animals to profile cellular ROS and antioxidant function, a workflow that is clearly not translatable to patients in clinical trials.…”

Antioxidant Therapy in Parkinson’s Disease: Insights from Drosophila melanogaster

“…Transgenic fly lines harbouring these advanced sensors have been already used to explore the in vivo redox changes occurring in normal physiology and in pathological states [59,61]. For example, the use of the mitochondrially targeted H 2 O 2 -sensitive probes has shown that this ROS species is increased in both Pink1 and parkin mutants, supporting the existence of a dysregulated redox homeostasis in these PD models [62]. Therefore, the availability of fly lines carrying redox-sensitive probes could significantly contribute to elucidation of the complex role played by the redox homeostasis in such pathological conditions.…”

“…The picture in (C) was produced in our laboratory by generating flies that overexpress GFP in DA neurons via TH-GAL4 driver. The picture in (F) was adapted from Reference [62].…”

The STING pathway does not contribute to behavioural or mitochondrial phenotypes in Drosophila Pink1/parkin or mtDNA mutator models

“…This has been severely hampered by the lack of robust phenotypes in Pink1/Prkn knockout mice. In contrast, Drosophila models have provided substantial insights in this realm as fly Pink1/parkin mutants exhibit extensive disruption of the neuromuscular system presenting, amongst www.nature.com/scientificreports www.nature.com/scientificreports/ of the mutant phenotypes as a sensitive readout, have elucidated several important and conserved features of PINK1/Parkin biology [17][18][19][20][21]26 .…”

“…The Drosophila models have been highly informative for interrogating the physiological role of PINK1/Parkin, primarily via genetic or pharmacological manipulations [17][18][19][20][21] that can modify the robust neuromuscular phenotypes associated with loss of the Pink1/parkin orthologs [22][23][24][25] (for review see 26 ). Therefore, we sought to determine whether aberrant activation of the Sting-Relish immune signalling cascade may contribute to the neuromuscular degeneration phenotypes observed in Drosophila Pink1/parkin mutants.…”