Superoxide dismutating molecules rescue the toxic effects of PINK1 and parkin loss.
Alam, Sarah M
Hum Mol Genet
Oxford University Press (OUP)
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Biosa, A., Sanchez-Martinez, A., Filograna, R., Terriente-Felix, A., Alam, S. M., Beltramini, M., Bubacco, L., et al. (2018). Superoxide dismutating molecules rescue the toxic effects of PINK1 and parkin loss.. Hum Mol Genet, 27 (9), 1618-1629. https://doi.org/10.1093/hmg/ddy069
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.
Hela Cells, Humans, Parkinson Disease, Manganese, Reactive Oxygen Species, Organometallic Compounds, Ubiquitin-Protein Ligases, Superoxide Dismutase, Protein Kinases, Blotting, Western, Oxidative Stress, HEK293 Cells, Superoxide Dismutase-1
Medical Research Council (MC_UP_1501/1)
Medical Research Council (MC_UU_00015/6)
European Research Council (309742)
Embargo Lift Date
External DOI: https://doi.org/10.1093/hmg/ddy069
This record's URL: https://www.repository.cam.ac.uk/handle/1810/277780
Attribution 4.0 International
Licence URL: http://creativecommons.org/licenses/by/4.0/