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Oxidative stress induced by loss of Cu,Zn-superoxide dismutase (SOD1) or superoxide-generating herbicides causes axonal degeneration in mouse DRG cultures

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Abstract

Axonal degeneration is a common pathologic feature in peripheral neuropathy, neurodegenerative disease, and normal aging. Oxidative stress may be an important mechanism of axonal degeneration, but is underrepresented among current experimental models. To test the effects of loss of the antioxidant enzyme Cu,Zn-superoxide dismutase (SOD1) on axon survival, we cultured dorsal root ganglion (DRG) neurons from SOD1 knockout mice. Beginning as early as 48–72 h, we observed striking degeneration of Sod1−/− axons that was prevented by introduction of human SOD1 and was attenuated by antioxidant treatment. To test susceptibility to increased superoxide production, we exposed wild-type DRGs to the redox-cycling herbicides paraquat and diquat (DQ). Dose-dependent axon degeneration was observed, and toxicity of DQ was exacerbated by SOD1 deficiency. MTT staining suggested that DRG axons are more susceptible to injury than their parent cell bodies in both paradigms. Taken together, these data demonstrate susceptibility of DRG axons to oxidative stress-mediated injury due to loss of SOD1 or excess superoxide production. These in vitro models provide a novel means of investigating oxidative stress-mediated injury to axons, to improve our understanding of axonal redox control and dysfunction in peripheral neuropathy.

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Acknowledgments

We are grateful to Marie Csete for providing Sod1−/− breeders and low oxygen culture equipment, to Minsheng Wang for instruction on DRG cultures, and to Seneshaw Asress for technical assistance. This work was supported by a grant from the Packard Center for ALS Research and by NIH T32 training grant ES12870 (LF).

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  1. Department of Neurology, Emory University School of Medicine, Atlanta, GA, 30322, USA

    Lindsey R. Fischer

  2. Departments of Neurology, Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, 30322, USA

    Jonathan D. Glass

  3. Emory Center for Neurodegenerative Disease, Whitehead Biomedical Research Building, 615 Michael Street, 5th Floor, Mailstop 1941007001, Atlanta, GA, 30322, USA

    Jonathan D. Glass

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Fischer, L.R., Glass, J.D. Oxidative stress induced by loss of Cu,Zn-superoxide dismutase (SOD1) or superoxide-generating herbicides causes axonal degeneration in mouse DRG cultures. Acta Neuropathol 119, 249–259 (2010). https://doi.org/10.1007/s00401-009-0631-z

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