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

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-Daspartate (NMDA) receptor (NMDAR) activation and subsequent Ca 2 þ 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 SNODrp1). 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.

The protein disulfide isomerases PDIA4 and PDIA6 mediate resistance to cisplatin-induced cell death in lung adenocarcinoma

“…41 It is also known that intracellular redistribution of PDIs or modification of its redox activity can be controlled by N-nitrosylation in conditions of nitrosative stress. [42][43][44] Therefore, it is tempting to speculate that in patient biopsies PDIA6 might redistribute intracellularly as a consequence of yet-to-be elucidated post-translational modifications. The cytosolic location of PDIA6 in CDDP-treated tumors could suggest their role in the DNA damage signaling cascade and provide a novel promising target for chemotherapeutic intervention.…”

Post-translational add-ons mark the path in exosomal protein sorting

“…Tyr 46.006 -// Denitrase [163] S-NitrosylaƟon Nitric oxide (NO) C ys (1,2) Met 30.006 Nytrosylases // Denitrosylases, SNitroglutathione reductase (GSNOR) [164] Other oxidaƟve compound: hydrogen peroxide (peroxidaƟon) and nitrate. [161] SulfaƟon Sulphate [183] PolyglycylaƟon G lycine (up to 34) Glu > 75.067 G lycylase // Deglycylase [184,185] Other: CitrullinaƟon (conversion of Arg to citrulline by PAD enzyme) [186,187] [21,22,14 7] M1/K63 PolyUB Chain: C-t bond with N-t Met, Lys63 > 8565 [88,147] K6/K29/K33 PolyUB Chain: C-t bond with Lys6/Lys29/ Lys33 > 8565 K11/K27/K48 PolyUB Chain: C-t bond with Lys11/Lys27/ Lys48 > 8565…”

Identification of NCF2/p67phox as a novel p53 target gene

“…[65][66][67][68][69] However, it is now accepted that ROS may have an important role in regulating signal transduction pathways, gene expression and differentiation, although the molecular mechanisms upstream and downstream ROS generation are not fully understood. [70][71][72][73][74][75] The main nonmitochondrial sources of ROS are the NADPH oxidases, which are membrane-associated multi-protein complexes, of which NFC2/p67phox is an essential and crucial component, which produce superoxide.…”