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Inducible nitric oxide synthase is present in motor neuron mitochondria and Schwann cells and contributes to disease mechanisms in ALS mice

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Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease of motor neurons (MNs). The molecular pathogenesis of ALS is not understood, thus effective therapies for this disease are lacking. Some forms of ALS are inherited by mutations in the superoxide dismutase-1 (SOD1) gene. Transgenic mice expressing human Gly93 → Ala (G93A) mutant SOD1 (mSOD1) develop severe MN disease, oxidative and nitrative damage, and mitochondrial pathology that appears to involve nitric oxide-mediated mechanisms. We used G93A-mSOD1 mice to test the hypothesis that the degeneration of MNs is associated with an aberrant up-regulation of the inducible form of nitric oxide synthase (iNOS or NOS2) activity within MNs. Western blotting and immunoprecipitation showed that iNOS protein levels in mitochondrial-enriched membrane fractions of spinal cord are increased significantly in mSOD1 mice at pre-symptomatic stages of disease. The catalytic activity of iNOS was also increased significantly in mitochondrial-enriched membrane fractions of mSOD1 mouse spinal cord at pre-symptomatic stages of disease. Reverse transcription-PCR showed that iNOS mRNA was present in the spinal cord and brainstem MN regions in mice and was increased in pre-symptomatic and early symptomatic mice. Immunohistochemistry showed that iNOS immunoreactivty was up-regulated first in spinal cord and brainstem MNs in pre-symptomatic and early symptomatic mice and then later in the course of disease in numerous microglia and few astrocytes. iNOS accumulated in the mitochondria in mSOD1 mouse MNs. iNOS immunoreactivity was also up-regulated in Schwann cells of peripheral nerves and was enriched particularly at the paranodal regions of the nodes of Ranvier. Drug inhibitors of iNOS delayed disease onset and significantly extended the lifespan of G93A-mSOD1 mice. This work identifies two new potential early mechanisms for MN degeneration in mouse ALS involving iNOS at MN mitochondria and Schwann cells and suggests that therapies targeting iNOS might be beneficial in treating human ALS.

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Acknowledgments

The authors thank Yan Pan, Ann Price, and Debora Flock for their technical assistance. This work was supported by grants from the US Public Health Service, NIH-NINDS (NS065895, NS052098) and NIH-NIA (AG016282).

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  1. Division of Neuropathology, Department of Pathology, Johns Hopkins University School of Medicine, 558 Ross Building, 720 Rutland Avenue, Baltimore, MA, 21205-2196, USA

    Kevin Chen & Lee J. Martin

  2. Pathobiology Graduate Program, Johns Hopkins University School of Medicine, Baltimore, MA, USA

    Lee J. Martin

  3. Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MA, USA

    Lee J. Martin

  4. Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MA, USA

    Frances J. Northington

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  1. Kevin Chen
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Chen, K., Northington, F.J. & Martin, L.J. Inducible nitric oxide synthase is present in motor neuron mitochondria and Schwann cells and contributes to disease mechanisms in ALS mice. Brain Struct Funct 214, 219–234 (2010). https://doi.org/10.1007/s00429-009-0226-4

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