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

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 (RNF213) 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.