New insights into the regulation of Cystathionine beta synthase (CBS), an enzyme involved in intellectual deficiency in Down syndrome

Abstract

Down syndrome (DS), the most frequent chromosomic aberration, results from the presence of an extra copy of chromosome 21. The identification of genes which overexpression contributes to intellectual disability (ID) in DS is important to understand the pathophysiological mechanisms involved and develop new pharmacological therapies. In particular, gene dosage of Dual specificity tyrosine phosphorylation Regulated Kinase 1A (DYRK1A) and of Cystathionine beta synthase (CBS) are crucial for cognitive function. As these two enzymes have lately been the main targets for therapeutic research on ID, we sought to decipher the genetic relationship between them. We also used a combination of genetic and drug screenings using a cellular model overexpressing CYS4, the homolog of CBS in Saccharomyces cerevisiae, to get further insights into the molecular mechanisms involved in the regulation of CBS activity. We showed that overexpression of YAK1, the homolog of DYRK1A in yeast, increased CYS4 activity whereas GSK3β was identified as a genetic suppressor of CBS. In addition, analysis of the signaling pathways targeted by the drugs identified through the yeast-based pharmacological screening, and confirmed using human HepG2 cells, emphasized the importance of Akt/GSK3β and NF-κB pathways into the regulation of CBS activity and expression. Taken together, these data provide further understanding into the regulation of CBS and in particular into the genetic relationship between DYRK1A and CBS through the Akt/GSK3β and NF-κB pathways, which should help develop more effective therapies to reduce cognitive deficits in people with DS.

Bioinformatics analysis of the clinical value and potential mechanisms of CBS/H2S in Glioma through 1027 samples.

“…Furthermore,data from functional studies of glioma based on GO and GSVA revealed that CBS is positvely involved with nervous development,notch pathway and metabolism pathway (4). Through the NF-κB and Akt/ GSK3β pathway,the expression and activity of CBS play a crucial role in signi cantly alleviating cognitive de cits in individuals with Down syndrome (20).Derease of CBS/H2S level in hunman brain of Alzheimer's disease (AD)was published (21), the cognitive impairment can be ameliorated by H2S doners through the activation of the PI3/Akt signaling pathway (22).Several reports have also been dedicated to investigating the association between CBS/H2S pathway and notch pathway.A previous study demonstrated that high CBS/H2S sysytem expression facilitates the proliferation of esophageal squamous cell carcinoma (ESCC) via interrupt the Notch1/Hes1 axis (23).…”

Rapid effects of valproic acid on the fetal brain transcriptome: Implications for brain development and autism

“…In fact, several genes triplicated in DS that have been liked to autism are up-or downregulated by VPA in the fetal brain; these include Dyrk1a (−1.5), Brwd1 (−1.3) and Cbs (+5.0) (Park and Chung, 2013;Duchon and Herault, 2016;Fulton et al, 2022;Marechal et al, 2019). ID in both ASDs and DS has been attributed to overexpression of Cbs (cystathionine beta synthase) (Conan et al, 2023;Tisato et al, 2021); dysregulation of Cbs and dihydrofolate reductase (Dhfr, +1.5) contributes to inborn errors of amino acid metabolism and is linked to ASDs (Zigman et al, 2021;Hoxha et al, 2021). Dyrk1a (which encodes dual specificity tyrosine phosphorylation regulated kinase 1A) is believed to underlie intellectual disability in DS due to its increased gene dosage in DS (Duchon and Herault, 2016).…”