The study of the metabolic pathways implicated in Down syndrome (DS) is being studied but still lacking some answers. The team led by Pr Csaba Szabo evidenced the role of CBS protein and its pathway (leading to H₂S production) in neurobehavioral troubles in a murine model of DS: Dp(17)3Yey/+ mice overexpressing Cbs gene. In this recently published article, Theodora Panagaki and authors showed an increased expression of Cbs in murine Dp(17) brains, especially in astrocytes. These cells are key supporting cells for synaptic plasticity and metabolic support of neurons, among other roles. These mice also present an increased reactive astrogliosis that is suppressed when they are administered a CBS inhibitor (AOAA). Concerning cognitive functions, mice overexpressing Cbs present an impaired recognition memory (more pronounced in females) and an altered spatial memory. Synaptic function is impaired, along with bioenergetic defects. In addition to these troubles, DS mice have dysregulated UPR and autophagy pathways that are normalized and corrected by AOAA treatment. Metabolomic analysis of the DS mouse brain is significantly different from WT brains. H₂S levels were also found to be higher at the brain and plasma levels in comparison to controls. Treatment with AOAA improves neurobehavioral function and some metabolic troubles of the synaptic function in DS mice. Thus, this article confirms the role of CBS/H₂S pathway in neuro-cellular dysfunction observed in DS, with a curious and unexplained sex variability, not found at whole-body level. These promising results strengthen the need to pursue CBS study to decipher its biological implications. The Fondation Jérôme Lejeune is proud to sponsor this research program that holds out the promise of further advances for people with Down syndrome.

Panagaki, T., Janickova, L., Petrovic, D. et al. Neurobehavioral dysfunction in a mouse model of Down syndrome: upregulation of cystathionine β-synthase, H2S overproduction, altered protein persulfidation, synaptic dysfunction, endoplasmic reticulum stress, and autophagy. GeroScience (2024). https://doi.org/10.1007/s11357-024-01146-8