Inhibition of Gsk3b Reduces Nfkb1 Signaling and Rescues Synaptic Activity to Improve the Rett Syndrome Phenotype in Mecp2-Knockout Mice

Abstract

Rett syndrome (RTT) is the second leading cause of mental impairment in girls and is currently untreatable. RTT is caused, in more than 95% of cases, by loss-of-function mutations in the methyl CpG-binding protein 2 gene (MeCP2). We propose here a molecular target involved in RTT: the glycogen synthase kinase-3b (Gsk3b) pathway. Gsk3b activity is deregulated in Mecp2-knockout (KO) mice models, and SB216763, a specific inhibitor, is able to alleviate the clinical symptoms with consequences at the molecular and cellular levels. In vivo, inhibition of Gsk3b prolongs the lifespan of Mecp2-KO mice and reduces motor deficits. At the molecular level, SB216763 rescues dendritic networks and spine density, while inducing changes in the properties of excitatory synapses. Gsk3b inhibition can also decrease the nuclear activity of the Nfkb1 pathway and neuroinflammation. Altogether, our findings indicate that Mecp2 deficiency in the RTT mouse model is partially rescued following treatment with SB216763.

Altered inflammasome machinery as a key player in the perpetuation of Rett syndrome oxinflammation

“…A study by Kishi and colleagues [52] on the cortex of Mecp2 -null mice demonstrated an abnormal upregulation of NF-κB signaling, which reduction ameliorated the dendritic complexity of callosal projection neurons and prolonged their normal lifespan. Similarly, a marked decrease in inflammation markers was observed in the cerebellar area of Mecp2 -knockout mice after treatment with a specific glycogen synthase kinase-3b (Gsk3b) inhibitor that attenuated the nuclear NF-κB activity [53]. Together, these evidence and our results suggest the hypothesis that NF-κB pathway dysregulation could play a significant role in RTT pathophysiology, as already proven in rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, atherosclerosis, systemic lupus erythematosus, type I diabetes, chronic obstructive pulmonary disease and asthma [54].…”

<p>Aberrantly High Expression Of NOK/STYK1 Is Tightly Associated With The Activation Of The AKT/GSK3β/N-Cadherin Pathway In Non-Small Cell Lung Cancer</p>

“…Then, the sections were microwaved in 10 mM citrate buffer (pH 6.0) at 95°C for 20 min to perform antigen retrieval. After being blocked with goat serum for 30 min, the sections were incubated with the primary antibody (anti-Styk1 ab97451, 20 anti-AKT1 (phospho S473) ab81283, 21 anti-pan-AKT (phospho T308) ab38449, 22 anti-GSK3 beta (phospho Y216) ab75745, 23 anti-GSK3 beta (phospho S9) ab75814, 24 anti-E Cadherin ab40772 25,26 from Abcam, Cambridge, UK; and N-cadherin (D4R1H) 27 from Cell Signaling Technology, Danvers, MA, USA) at 4°C overnight. After being washed in PBS (phosphate-buffered saline), the sections were incubated with the appropriate horseradish peroxidase (HRP)-labeled goat anti-rabbit/mouse antibodies.…”

Principles of mRNA control by human PUM proteins elucidated from multi-modal experiments and integrative data analysis

“…For instance, the guanyl-nucleotide exchange factor activity GO term (GO:0005085; Figure 5C, far-left) includes guanine nucleotide exchange factors (GEFs) which activate Rho-family GTPases to regulate a diverse suite of cellular functions, including cell-cycle progression, the actin cytoskeleton, and transcription [72]. Additionally, genes involved in peptidyl-serine phosphorylation (GO:0018105; Figure 5C, mid-left), represent a broad class of kinases, including those involved in neurological disease and inflammation [63, 73]. Finally genes involved in transcriptional repressor activity (GO:0001078, Figure 5C, mid-right), include proteins involved in regulating hematopoiesis and controlling neurological development [74–76].…”