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Redox Reactions Induced by Nitrosative Stress Mediate Protein Misfolding and Mitochondrial Dysfunction in Neurodegenerative Diseases

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Abstract

Overstimulation of N-methyl-d-aspartate (NMDA)-type glutamate receptors accounts, at least in part, for excitotoxic neuronal damage, potentially contributing to a wide range of acute and chronic neurologic diseases. Neurodegenerative disorders including Alzheimer’s disease (AD) and Parkinson’s disease (PD), manifest deposits of misfolded or aggregated proteins, and result from synaptic injury and neuronal death. Recent studies have suggested that nitrosative stress due to generation of excessive nitric oxide (NO) can mediate excitotoxicity in part by triggering protein misfolding and aggregation, and mitochondrial fragmentation in the absence of genetic predisposition. S-Nitrosylation, or covalent reaction of NO with specific protein thiol groups, represents a convergent signal pathway contributing to NO-induced protein misfolding and aggregation, compromised dynamics of mitochondrial fission-fusion process, thus leading to neurotoxicity. Here, we review the effect of S-nitrosylation on protein function under excitotoxic conditions, and present evidence suggesting that NO contributes to protein misfolding and aggregation via S-nitrosylating protein-disulfide isomerase or the E3 ubiquitin ligase parkin, and mitochondrial fragmentation through β-amyloid-related S-nitrosylation of dynamin-related protein-1. Moreover, we also discuss that inhibition of excessive NMDA receptor activity by memantine, an uncompetitive/fast off-rate (UFO) drug can ameliorate excessive production of NO, protein misfolding and aggregation, mitochondrial fragmentation, and neurodegeneration.

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Acknowledgements

This work was supported in part by the MU Start-up fund, the American Heart Association grants 0665051Y and 09SDG2260983, The Dana Foundation, and NIH 5P01 ES016738-02 Consortium (to Z.G.); NIH grants P01 HD29587, R01 EY05477, R01 EY09024, the American Parkinson’s Disease Association, San Diego Chapter, and an Ellison Senior Scholars Award in Aging (to S.A.L.).

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  1. Department of Pathology and Anatomical Sciences, University of Missouri-Columbia School of Medicine, One Hospital Drive, Columbia, MO, 65212, USA

    Zezong Gu

  2. Center for Neuroscience, Aging and Stem Cell Research, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA, 92037, USA

    Zezong Gu, Tomohiro Nakamura & Stuart A. Lipton

  3. Department of Neurosciences, University of California at San Diego, 9500 Gilman Drive, La Jolla, CA, 92039, USA

    Stuart A. Lipton

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  1. Zezong Gu
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Correspondence to Zezong Gu or Stuart A. Lipton.

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Gu, Z., Nakamura, T. & Lipton, S.A. Redox Reactions Induced by Nitrosative Stress Mediate Protein Misfolding and Mitochondrial Dysfunction in Neurodegenerative Diseases. Mol Neurobiol 41, 55–72 (2010). https://doi.org/10.1007/s12035-010-8113-9

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