Dodecyl creatine ester improves cognition in mouse model of CTD

Abstract: Creatine transporter deficiency (CTD), a leading cause of intellectual disability is a result of the mutation in the gene encoding the creatine transporter SLC6A8, which prevents creatine uptake into the brain, causing mental retardation, expressive speech and language delay, autistic-like behavior and epilepsy. Preclinical in vitro and in vivo data indicate that dodecyl creatine ester (DCE) which increases the creatine brain content, might be a therapeutic option for CTD patients. To gain a better understanding of the pathophysiology and DCE treatment efficacy in CTD, this study focuses on the identification of biomarkers related to cognitive improvement in a Slc6a8 knockout mouse model (Slc6a8−/y) engineered to mimic the clinical features of CTD patients which have low brain creatine content.

Parent Summary: Mabondzo and colleagues used a mouse model of CTD to better understand (1) which proteins are related to CTD and (2) whether treatment with dodecyl creatine ester (DCE) changes the amount of those proteins in the brain. (As background, in March 2021, dodecyl creatine ester was suggested to the FDA as a possible treatment for CTD, but it has not yet been approved by the FDA for this purpose.) DCE was given through the nose to a group of mice that did not express the SLC6A8 gene (which needs to be expressed for creatine transport to happen); mice that do not express (or have mutations in) the SLC6A8 gene are called “SLC6A8 knockout” mice in scientific papers. SLC6A8 knockout mice that were given DCE showed significant improvements in cognition, similar to the mice that did express SLC6A8. In the brains of these same mice, the authors identified 14 different proteins that were altered by SLC6A8 expression and by being given DCE. (Interestingly, 13 of these 14 proteins have been shown to be related to other disorders characterized by intellectual disability, such as autism). For example, in the SLC6A8 knockout mice, there was a large amount of the KIF1A protein, and the mice that showed a greater amount of this protein showed lower cognition. Overall, these results suggest that K1F1A (as well as another protein, PLCB1) may be an important mechanism related to CTD and that treatment with DCE may help restore cognitive deficits of CTD.

Link to article: https://www.frontiersin.org/articles/10.3389/fnmol.2023.1118707/full

Link to PubMed: https://pubmed.ncbi.nlm.nih.gov/37063368/

Authors: Aloïse Mabondzo, Rania Harati, Léa Broca-Brisson, Anne-Cécile Guyot, Narciso Costa, Francesco Cacciante, Elena Putignano, Laura Baroncelli, Matthew R. Skelton, Cathy Saab, Emmanuelle Martini, Henri Benech, Thomas Joudinaud, Jean-Charles Gaillard, Jean Armengaud and Rifat Hamoudi

Key Terms: CTD, animal models, small molecule therapy, therapeutics, basic science, mutation study, diagnostic, in vitro