AUTHOR=Conan Pierre , Léon Alice , Caroff Noéline , Rollet Claire , Chaïr Loubna , Martin Jennifer , Bihel Frédéric , Mignen Olivier , Voisset Cécile , Friocourt Gaëlle 

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

JOURNAL=Frontiers in Neuroscience

VOLUME=16

YEAR=2023

URL=https://www.frontiersin.org/journals/neuroscience/articles/10.3389/fnins.2022.1110163

DOI=10.3389/fnins.2022.1110163

ISSN=1662-453X

ABSTRACT=<p>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 <italic>Dual specificity tyrosine phosphorylation Regulated Kinase 1A</italic> (<italic>DYRK1A</italic>) and of <italic>Cystathionine beta synthase</italic> (<italic>CBS</italic>) 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 <italic>CYS4</italic>, the homolog of <italic>CBS</italic> in <italic>Saccharomyces cerevisiae</italic>, to get further insights into the molecular mechanisms involved in the regulation of CBS activity. We showed that overexpression of <italic>YAK1</italic>, the homolog of <italic>DYRK1A</italic> in yeast, increased <italic>CYS4</italic> activity whereas <italic>GSK3</italic>β was identified as a genetic suppressor of <italic>CBS</italic>. 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 <italic>DYRK1A</italic> and <italic>CBS</italic> through the Akt/GSK3β and NF-κB pathways, which should help develop more effective therapies to reduce cognitive deficits in people with DS.</p>