Manganese Superoxide Dismutase Protects nNOS Neurons from NMDA and Nitric Oxide-Mediated Neurotoxicity

Mirella Gonzalez-Zulueta; Lisa M. Ensz; Galina Mukhina; Russell M. Lebovitz; Ralf M. Zwacka; John F. Engelhardt; Larry W. Oberley; Valina L. Dawson; Ted M. Dawson

doi:10.1523/JNEUROSCI.18-06-02040.1998

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Manganese Superoxide Dismutase Protects nNOS Neurons from NMDA and Nitric Oxide-Mediated Neurotoxicity

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Manganese Superoxide Dismutase Protects nNOS Neurons from NMDA and Nitric Oxide-Mediated Neurotoxicity

Mirella Gonzalez-Zulueta, Lisa M. Ensz, Galina Mukhina, Russell M. Lebovitz, Ralf M. Zwacka, John F. Engelhardt, Larry W. Oberley, Valina L. Dawson and Ted M. Dawson

The Journal of neuroscience, Vol.18(6), pp.2040-2055

03/15/1998

DOI: 10.1523/JNEUROSCI.18-06-02040.1998

PMCID: PMC6792928

PMID: 9482791

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Abstract

Neuronal nitric oxide synthase (nNOS) neurons kill adjacent neurons through the action of NMDA-glutamate receptor activation, although they remain relatively resistant to the toxic effects of NMDA and NO. The molecular basis of the resistance of nNOS neurons to toxic insults is unknown. To begin to understand the molecular mechanisms of the resistance of nNOS neurons, we developed a pheochromacytoma-derived cell line (PC12) that is resistant to the toxic effects of NO. We found through serial analysis of gene expression (SAGE) that manganese superoxide dismutase (MnSOD) is enriched in the NO-resistant PC12 cell-derived line (PC12-R). Antisense MnSOD renders PC12-R cells sensitive to NO toxicity and increases the sensitivity to NO in the parental, NO-sensitive PC12 line (PC12-S). Adenoviral transfer of MnSOD protects PC12-S cells against NO toxicity. We extended these studies to cortical cultures and showed that MnSOD is enriched in nNOS neurons and that antisense MnSOD renders nNOS neurons susceptible to NMDA neurotoxicity, although it has little effect on the overall susceptibility of cortical neurons to NMDA toxicity. Overexpression of MnSOD provides dramatic protection against NMDA and NO toxicity in cortical cultures, but not against kainate or AMPA neurotoxicity. Furthermore, nNOS neurons from MnSOD −/− mice are markedly sensitive to NMDA toxicity. Adenoviral transfer of MnSOD to MnSOD −/− cultures restores resistance of nNOS neurons to NMDA toxicity. Thus, MnSOD is a major protective protein that appears to be essential for the resistance of nNOS neurons in cortical cultures to NMDA mediated neurotoxicity.

MnSOD

neurodegenerative diseases

nitric oxide

NMDA toxicity

nNOS neuron

resistance to nitric oxide

Details

Title: Subtitle: Manganese Superoxide Dismutase Protects nNOS Neurons from NMDA and Nitric Oxide-Mediated Neurotoxicity
Creators: Mirella Gonzalez-Zulueta - Johns Hopkins Medicine
Lisa M. Ensz - Departments of Neurology,
Galina Mukhina - Departments of Neurology,
Russell M. Lebovitz - Baylor College of Medicine
Ralf M. Zwacka - University of Iowa
John F. Engelhardt - University of Iowa
Larry W. Oberley - University of Iowa
Valina L. Dawson - Johns Hopkins Medicine
Ted M. Dawson - Departments of Neurology,
Resource Type: Journal article
Publication Details: The Journal of neuroscience, Vol.18(6), pp.2040-2055
DOI: 10.1523/JNEUROSCI.18-06-02040.1998
PMID: 9482791
PMCID: PMC6792928
NLM abbreviation: J Neurosci
ISSN: 0270-6474
eISSN: 1529-2401
Publisher: Society for Neuroscience
Language: English
Date published: 03/15/1998
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Anatomy and Cell Biology; Radiation Oncology; Internal Medicine
Record Identifier: 9984284354602771

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