Redox reactions induced by nitrosative stress mediate protein misfolding and mitochondrial dysfunction in neurodegenerative diseases

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 beta-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.

Fig. 1

Possible mechanism whereby S-nitrosylated species contribute to the accumulation of aberrant proteins and mitochondrial fragmentation. NMDAR hyperactivation triggers generation of NO/ROS and cytochrome C release from mitochondria associated with subsequent activation of caspases, causing neuronal cell damage and death. S-nitrosylation of parkin (forming SNO-PARK) and PDI (forming SNO-PDI) can contribute to neuronal cell injury in part by triggering accumulation of misfolded proteins, whereas SNO-Drp1 mediates Aβ-related excessive mitochondrial fission and synaptic injury. Memantine and NitroMemantine preferentially block overstimulated (pathological/extrasynaptic) NMDAR activity while relatively sparing normal (physiological/synaptic) activity l

Fig. 2

Atomic-resolution model of Drp1 for its S-nitrosylation motif. a Domain comparison of GTPase family members—dynamin and Drp-1. GTPase GTPase domain, Dynamin M dynamin-like middle domain, GED GTPase effector domain, PH pleckstrin homology domain. b Atomic resolution model of Drp1 superimposed onto electron density map of homologous domains of dynamin dimer: GTPase (yellow), forming the head; Dynamin M (green), and GED (magenta) domains, forming the stalk. c Predicted ribbon model structure of human Drp1 showing putative acid/base S-nitrosylation motif around Cys644 (yellow). C Cys, E Glu (red for negatively charged surface), K Lys (blue for positively charged surface)