Redox modulation by S-nitrosylation contributes to protein misfolding, mitochondrial dynamics, and neuronal synaptic damage in neurodegenerative diseases

Del E. Webb Center for Neuroscience, Aging, and Stem Cell Research, Sanford-Burnham Medical Research Institute,10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
Cell death and differentiation (Impact Factor: 8.39). 05/2011; 18(9):1478-86. DOI: 10.1038/cdd.2011.65
Source: PubMed

ABSTRACT The pathological processes of neurodegenerative disorders such as Alzheimer's and Parkinson's diseases engender synaptic and neuronal cell damage. While mild oxidative and nitrosative (nitric oxide (NO)-related) stress mediates normal neuronal signaling, excessive accumulation of these free radicals is linked to neuronal cell injury or death. In neurons, N-methyl-D-aspartate (NMDA) receptor (NMDAR) activation and subsequent Ca(2+) influx can induce the generation of NO via neuronal NO synthase. Emerging evidence has demonstrated that S-nitrosylation, representing covalent reaction of an NO group with a critical protein thiol, mediates the vast majority of NO signaling. Analogous to phosphorylation and other posttranslational modifications, S-nitrosylation can regulate the biological activity of many proteins. Here, we discuss recent studies that implicate neuropathogenic roles of S-nitrosylation in protein misfolding, mitochondrial dysfunction, synaptic injury, and eventual neuronal loss. Among a growing number of S-nitrosylated proteins that contribute to disease pathogenesis, in this review we focus on S-nitrosylated protein-disulfide isomerase (forming SNO-PDI) and dynamin-related protein 1 (forming SNO-Drp1). Furthermore, we describe drugs, such as memantine and newer derivatives of this compound that can prevent both hyperactivation of extrasynaptic NMDARs as well as downstream pathways that lead to nitrosative stress, synaptic damage, and neuronal loss.

  • Source
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Many researchers have reported that oxidative damage to mitochondrial DNA (mtDNA) is increased in several age-related disorders. Damage to mitochondrial constituents and mtDNA can generate additional mitochondrial dysfunction that may result in greater reactive oxygen species production, triggering a circular chain of events. However, the mechanisms underlying this vicious cycle have yet to be fully investigated. In this review, we summarize the relationship of oxidative stress-induced mitochondrial dysfunction with mtDNA mutation in neurodegenerative disorders.
    Experimental and Molecular Medicine 03/2015; 47(3):e150-. DOI:10.1038/emm.2014.122 · 2.46 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Early degeneration of pedunculopontine nucleus (PPN) is considered part of the changes that characterize premotor stages of Parkinson's disease (PD). In this paper, the effect of unilateral neurotoxic lesion of PPN in motor execution and in the development of oxidative stress events in striatal and nigral tissues in rats were evaluated. The motor performance was assessed using the beam test (BT) and the cylinder test (CT). Nigral and striatal redox balance, was studied by means of biochemical indicators such as malondialdehyde (MDA), nitric oxide (NO) and the catalase enzymatic activity (CAT EA). Lesioned rats showed fine motor dysfunction expressed both as an increase in the length (p<0.001) and deviation (p<0.001) of the traveled path and also in the time spent (p<0.01) in the circular small beam (CBS) (p<0.01) in comparison with control groups. In addition, the lesioned rats group presented a right asymmetry index greater than 0.5 which is consistent with a significant increase in the percentage of use of the right forelimb (ipsilateral to the lesion), compared with control group (p<0.05). Biochemical studies revealed that after 48h PPN neurotoxic injury, the CAT EA showed a significant increase in the subtantia nigra pars compacta (SNpc) (p<0.05). This significant increase of CAT EA persisted in the nigral tissue (p<0.001) and reached the striatal tissue (p<0.001) seven days after PPN injury. Also at seven days post-injury PPN, increased concentrations of MDA (p<0.01) and a tendency to decrease in the concentrations of NO in both structures (SNpc and striatum) was found. The events associated with the generation of free radicals at nigral and striatal level, can be part of the physiological mechanisms underlying motor dysfunction in rats with unilateral PPN neurotoxic lesion. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.
    Neuroscience 01/2015; 289. DOI:10.1016/j.neuroscience.2014.12.056 · 3.33 Impact Factor


Available from