S-nitrosylation of E3 ubiquitin-protein ligase RNF213 alters non-canonical Wnt/Ca+2 signaling in the P301S mouse model of tauopathy

Abstract

Mutations in the MAPT gene, which encodes the tau protein, are associated with several neurodegenerative diseases, including frontotemporal dementia (FTD), dementia with epilepsy, and other types of dementia. The missense mutation in the Mapt gene in the P301S mouse model of FTD results in impaired synaptic function and microgliosis at three months of age, which are the earliest manifestations of disease. Here, we examined changes in the S-nitrosoproteome in 2-month-old transgenic P301S mice in order to detect molecular events corresponding to early stages of disease progression. S-nitrosylated (SNO) proteins were identified in two brain regions, cortex and hippocampus, in P301S and Wild Type (WT) littermate control mice. We found major changes in the S-nitrosoproteome between the groups in both regions. Several pathways converged to show that calcium regulation and non-canonical Wnt signaling are affected using GO and pathway analysis. Significant increase in 3-nitrotyrosine was found in the CA1 and entorhinal cortex regions, which indicates an elevation of oxidative stress and nitric oxide formation. There was evidence of increased Non-Canonical Wnt/Ca++ (NC-WCa) signaling in the cortex of the P301S mice; including increases in phosphorylated CaMKII, and S-nitrosylation of E3 ubiquitin-protein ligase RNF213 (RNF-213) leading to increased levels of nuclear factor of activated T-cells 1 (NFAT-1) and FILAMIN-A, which further amplify the NC-WCa and contribute to the pathology. These findings implicate activation of the NC-WCa pathway in tauopathy and provide novel insights into the contribution of S-nitrosylation to NC-WCa activation, and offer new potential drug targets for treatment of tauopathies.

Nitric oxide as a developmental and metabolic signal in filamentous fungi

“…It has been shown that NO regulates protein activities either through binding to transition metals of metalloproteins (metal nitrosylation) or covalent modification of cysteine ( S‐ nitrosylation) and tyrosine (tyrosine nitration) residues (Amal et al, ; Heinrich et al, ). In addition, NO can also function as an activator of soluble guanylate cyclase (sGC), a hemoprotein that has evolved to bind selectively to NO even in the presence of oxygen (Boon & Marletta, ).…”

Low Doses of Arsenic in a Mouse Model of Human Exposure and in Neuronal Culture Lead to S-Nitrosylation of Synaptic Proteins and Apoptosis via Nitric Oxide

“…NO has a critical role in synaptic transmission in the brain [12] and plays a major role in signaling through the activation of GMP cyclase [12], effects on ion transporters [12], and S-nitrosylation (SNO) of peptides and proteins [13,14]. Numerous examples of neuropathologies exist that involve nitrosative stress (for review see [15,16]), including Alzheimer's [17], Parkinson's [18] and Huntington's diseases [19]. In addition, we have recently demonstrated the involvement of NO, SNO, and nitration in a mouse model of autism based on the SHANK3 human mutation [20].…”

Quantitative proteomics of synaptosome S‐nitrosylation in Alzheimer’s disease

“…In general, the protocol applied in this study yields good comparability when compared to other studies on the synaptic proteome. Nevertheless, only a small overlap was found between the identified proteins and other studies on the SNO-proteome (Seneviratne et al 2016;Amal et al 2019). Yet, these studies analyzed whole-brain regions utilizing different models and enrichment strategies for nitrosylated peptides.…”

“…Studies carried out in NOS2 knockout mice have shown a correlation between NOS2, amyloid beta (Ab) deposition, and cognitive dysfunction in AD mouse models (Colton et al 2008;Kummer et al 2011). The SNO-proteome in cortex and hippocampus tissues is altered in both the CK-p25 mouse model of AD and the P301S mouse model of tauopathy (Seneviratne et al 2016;Amal et al 2019).…”