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Hum Mol Genet. 2019 Jan 10. doi: 10.1093/hmg/ddy447. [Epub ahead of print]

Cbs overdosage is necessary and sufficient to induce cognitive phenotypes in mouse models of Down syndrome and interacts genetically with Dyrk1a.

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Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, 1 rue Laurent Fries, 67404 Illkirch, France.
Centre National de la Recherche Scientifique, UMR7104, Illkirch, France.
Institut National de la Santé et de la Recherche Médicale, U1258, Illkirch, France.
Université de Strasbourg, Illkirch, France.
Inserm UMR 1078, Université de Bretagne Occidentale, Faculté de Médecine et des Sciences de la Santé, Etablissement Français du Sang (EFS) Bretagne, CHRU Brest, Hôpital Morvan, Laboratoire de Génétique Moléculaire, Brest, France.
Transgenese et Archivage Animaux Modèles, TAAM, CNRS, UPS44, 3B Rue de la Férollerie 45071 Orléans, France.
CELPHEDIA, PHENOMIN, Institut Clinique de la Souris, ICS, 1 Rue Laurent Fries, 67404 Illkirch, France.


Identifying dosage-sensitive genes is a key to understand the mechanisms underlying intellectual disability in Down syndrome (DS). The Dp(17Abcg1-Cbs)1Yah DS mouse model (Dp1Yah) shows cognitive phenotypes that need to be investigated to identify the main genetic driver. Here, we report that three copies of the cystathionine-beta-synthase gene (Cbs) in the Dp1Yah mice are necessary to observe a deficit in the novel object recognition (NOR) paradigm. Moreover, the overexpression of Cbs alone is sufficient to induce deficits in the NOR test. Accordingly, overexpressing human CBS specifically in Camk2a-expressing neurons leads to impaired objects discrimination. Altogether, this shows that Cbs overdosage is involved in DS learning and memory phenotypes. To go further, we identified compounds that interfere with the phenotypical consequence of CBS overdosage in yeast. Pharmacological intervention in Tg(CBS) mice with one selected compound restored memory in the NOR test. In addition, using a genetic approach, we demonstrated an epistatic interaction between Cbs and Dyrk1a, another human chromosome 21-located gene (which encodes the dual-specificity tyrosine phosphorylation-regulated kinase 1a) and an already known target for DS therapeutic intervention. Further analysis using proteomic approaches highlighted several molecular pathways, including synaptic transmission, cell projection morphogenesis and actin cytoskeleton, that are affected by DYRK1A and CBS overexpression. Overall, we demonstrated that CBS overdosage underpins the DS-related recognition memory deficit and that both CBS and DYRK1A interact to control accurate memory processes in DS. In addition, our study establishes CBS as an intervention point for treating intellectual deficiencies linked to DS.


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