The roles of S-nitrosylation and S-glutathionylation in Alzheimer's disease

Abstract

Alzheimer’s disease (AD) is a debilitating dementia with complex pathophysiological alterations including modifications to endogenous cysteine. S-nitrosylation (SNO) is a well-studied posttranslational modification (PTM) in the context of AD while S-glutathionylation (PSSG) remains less studied. Excess reactive oxygen and reactive nitrogen species (ROS/RNS) directly or indirectly generate SNO and PSSG. SNO is dysregulated in AD and plays a pervasive role in processes such as protein function, cell signaling, metabolism, and apoptosis. Despite some studies into the role of SNO in AD, multiple identified SNO proteins lack deep investigation and SNO modifications outside of brain tissues are limited, leaving the full role of SNO in AD to be elucidated. PSSG homeostasis is perturbed in AD and may affect a myriad of cellular processes. Here we overview the role of nitric oxide (NO•) in AD, discuss proteomic methodologies to investigate SNO and PSSG, and review SNO and PSSG in AD. A more thorough understanding of SNO, PSSG, and other cysteinyl PTMs in AD will be helpful for the development of novel therapeutics against neurodegenerative diseases.

Redox Post-translational Modifications of Protein Thiols in Brain Aging and Neurodegenerative Conditions—Focus on S-Nitrosation

“…Also, aberrant redox PTMs of proteins playing key roles in cell physiology are consistently observed in neurodegenerative conditions (Nakamura et al, 2013 ; Akhtar et al, 2016 ; Di Domenico et al, 2017 ; Tramutola et al, 2017 ; Valle and Carrì, 2017 ; Dyer et al, 2019 ; Sbodio et al, 2019 ; Tegeder, 2019 ; Nakamura and Lipton, 2020 ; Figures 2C–E ). For example, the redox-sensitive dynamin-related protein 1 (Drp1), a GTPase involved in mitochondrial fission, is activated by S-nitrosation (Drp1-SNO; Cho et al, 2009 ; Willems et al, 2015 ; Figure 2C ).…”

“…Levels of S-nitrosated Parkin are increased in postmortem tissues of patients with sporadic PD, which implicates S-nitrosation of Parkin in the pathophysiology of these forms of PD (Chung et al, 2004 ; Meng et al, 2011 ; Sunico et al, 2013 ). Therefore, O/N stresses-induced PTM of protein thiols has been proposed to play an important role in the pathophysiology of the most common forms of neurodegenerative conditions (Sabens Liedhegner et al, 2012 ; Nakamura et al, 2013 ; Valle and Carrì, 2017 ; Dyer et al, 2019 ).…”

Synthesis, Biomacromolecular Interactions, Photodynamic NO Releasing and Cellular Imaging of Two [RuCl(qn)(Lbpy)(NO)]X Complexes

“…Two new nitrosylruthenium complexes [RuCl(qn)(Lbpy)(NO)]X were synthesized based on 8-hydroxyquinoline and 2,2 -bipyridine ligands (Ru- naling pathways [8][9][10][11]. Studies show that NO is also involved in post-tran modifications and nitrosylation plays a vital role in regulating the function of cules and disease treatment [12,13].…”

“…At low nanomolar concentration, NO provides a pro-survival effect, while at relatively high µM level, it will arrest the cellular respiration and cause apoptosis in cancers on account of the inhibition of mitochondrial cytochrome c oxidase (CcO) or activated several pro-apoptotic caspase signaling pathways [ 8 , 9 , 10 , 11 ]. Studies show that NO is also involved in post-translational modifications and nitrosylation plays a vital role in regulating the function of biomolecules and disease treatment [ 12 , 13 ].…”

Context-dependent monoclonal antibodies against protein carbamidomethyl-cysteine

“…Examples include hemostatic proteins such as tissue factor, Thrombospondin-1 (gene:TSP1), Von Willebrand factor (gene:vWF), Plasmin, T-cell surface glycoprotein CD4 (gene:CD4), and integrin subtypes, reviewed by [2][3][4], (Cytokine receptor common subunit gamma (gene:CD132) [5], and select intracellular proteins such as transcription factors of the Ets family [6]. Proteins are also subject to irreversible post translational modification at cysteine sulfhydryl residues, including nitrosylation that underlies important functional changes in a number of proteins across broad biological systems [7][8][9]. Unravelling the biological roles of cysteine thiols and disulfides in specific proteins has been made possible through chemical methods that differentiate cysteine states.…”