Redox regulation of protein misfolding, mitochondrial dysfunction, synaptic damage, and cell death in neurodegenerative diseases

Abstract

The loss or injury of neurons associated with oxidative and nitrosative redox stress plays an important role in the onset of various neurodegenerative diseases. Specifically, nitric oxide (NO), can affect neuronal survival through a process called S-nitrosylation, by which the NO group undergoes a redox reaction with specific protein thiols. This in turn can lead to the accumulation of misfolded proteins, which generally form aggregates in Alzheimer's, Parkinson's, and other neurodegenerative diseases. Evidence suggests that S-nitrosylation can also impair mitochondrial function and lead to excessive fission of mitochondria and consequent bioenergetic compromise via effects on the activity of the fission protein dynamin-related protein 1 (Drp1). This insult leads to synaptic dysfunction and loss. Additionally, high levels of NO can S-nitrosylate a number of aberrant targets involved in neuronal survival pathways, including the antiapoptotic protein XIAP, inhibiting its ability to prevent apoptosis.

Fig. 1

Possible mechanisms whereby NO signaling regulates neuronal function. Hyperactivation of neuronal NMDARs can induce activation of neuronal NO synthase (nNOS) and thus production of NO. Glial cells (astrocytes and microglia) can also generate NO via iNOS expression or ROS-dependent inhibition of astrocytic glutamate uptake, which then activates neuronal NMDARs (Akama and Van Eldik, 2000; Lauderback et al., 1999; Li et al., 2009; Weldon et al., 1998). Additional mechanisms, such as mitochondrial dysfunction, may exist to promote NO production in the nervous system. Endothelial cells in the CNS vascular niche may also produce NO. NO thus generated can trigger formation of S-nitrosylated proteins. NO also activates soluble guanylate cyclase (sGC) to produce cGMP, which can activate cGMP-dependent protein kinase. Peroxynitrite (ONOO⁻), derived from reaction of NO and superoxide anion (O₂⁻·), can nitrate tyrosine residues to form 3-nitrotyrosine. Physiological levels of NO mediate neuroprotective effects, at least in part, by S-nitrosylating the NMDAR and caspases, thus inhibiting their activity. NO can also promote neuronal development via S-nitrosylation of HDAC2. In contrast, we and others have mounted evidence that overproduction of NO can be neurotoxic via S-nitrosylation of parkin, PDI, GAPDH, MMP-2/9, Cdk5, and Drp1. For instance, S-nitrosylated parkin and PDI contribute to neuronal cell injury by triggering accumulation of misfolded proteins, and S-nitrosylation of Drp1 causes excessive mitochondrial fragmentation and thus synaptic damage in neurodegenerative conditions. Additionally, since HSP-90 is a molecular chaperone and XIAP is a ubiquitin E3 ligase, S-nitrosylation of these proteins may contribute to protein misfolding and accumulation in degenerating neurons.