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Creatine transporter deficiency: use of two original models to characterize this rare genetic disease

Researchers at LENIT, in collaboration with Li2D (SPI/DMTS), have identified by mass spectrometry and bioinformatics analysis several biomarkers linked to the creatine transporter deficiency disorder (CTD) using two original models : mice with the clinical characteristics of CTD subjects and brain organoids derived from CTD patient cells, revealing new insights into the cellular and molecular mechanisms involved in this pathology.​

Published on 22 June 2023

​​Creatine transporter deficiency (CTD) is a rare metabolic and genetic disorder in which loss of functionality of the creatine transporter (SLC6A8) leads to a lack of creatine in the brain. It is characterised by disorders of the autistic sphere, intellectual deficits, major communication and developmental troubles, particularly in psychomotor development. Many children are also affected by epileptic seizures. This pathology, described in the early 2000s, is still largely under-diagnosed and affects mostly boys; it could account for 1 to 2% of mental retardation of unknown etiology.


In this publication, the researchers identified by mass spectrometry several biomarkers linked to cognitive improvement in mouse models presenting the clinical characteristics of patients with creatine transporter deficiency, treated with a dodecyl creatine ester​, a drug candidate currently under development.

Previous results from the team (Joliot 2019 highlight) indicate that intranasal administration of a dodecyl creatine ester (DCE) to SLC6a8-/y mice (an animal model of the disease that does not express the creatine transporter) is accompanied by an increase in creatine levels in the striatum, cerebellum, hippocampus and cortex, as well as an increase in synaptic markers in neuronal terminals, thus improving their cognitive function.
Here, the researchers set out to identify biomarkers linked to this cognitive improvement, in order to better understand the pathophysiology of CTD and explain at molecular level the efficacy of DCE treatment. To achieve this, they used a combination of cognitive tests (object recognition test, Y maze, Morris water maze) and large-scale molecular methods such as Shotgun proteomics. Analysis of 4035 proteins in four different brain regions (cerebellum, cortex, hippocampus, brainstem) was carried out on 24 animals. Results analyzed by integrative bioinformatics and statistical modeling identified several key CTD proteins, including KIF1A and PLCB1, whose abundance in different brain regions correlated significantly with improved cognitive tests in DCE-treated mice. The identification of other proteins suggests that CTD mice also present structural deficits (changes in neuronal migration or synaptogenesis).


In this publication, researchers have generated and characterized brain organoids derived from healthy subjects and patients with CTD, in which the expression and abundance of biomarkers of neural progenitor cells and neurogenesis are altered compared with organoids from healthy subjects.

The above results indicate that animal models appear to recapitulate the phenotype of CTD patients. However, inter-species differences complicate the extrapolation of results to humans, hence the importance of developing new models such as human organoids, which have become essential tools for biology and medicine.

In this second study, the researchers reprogrammed fibroblasts from CTD patients and healthy subjects into induced pluripotent stem cells (iPSCs), which have the capacity to differentiate into any cell type of the human body. The iPSCs thus obtained were then differentiated into cerebral organoids, constituting a mass of cells mimicking in vitro the structure and main functions of the human brain. After verifying that CTD brain organoids did indeed exhibit reduced creatine uptake and concentrations, the researchers again used Shotgun proteomics to compare the proteomes of healthy versus CTD organoids and identify the signaling pathways impacted. They revealed an altered signalling network, with similarities to other neuropathologies such as autism spectrum disorders, Down's syndrome and fragile X syndrome. These analyses also enabled the identification of major players impacting neurogenesis, such as the GSK3β kinase, and the modulation of certain brain proteins linked to the symptoms of CTD patients. Taken together, these results highlight a deficit in neurogenesis and synaptogenesis in these subjects, potential future therapeutic targets.


The results of these studies, on two experimental models of creatine transporter deficiency, constitute significant advances and contribute to an indisputable improvement in our understanding of the pathophysiology of CTD, offering new therapeutic targets and a solid basis for further research in this field.​

Contact : Aloïse Mabondzo ( )

- Shotgun proteomics refers to techniques for identifying proteins in complex mixtures using a combination of high-performance liquid chromatography and mass spectrometry.
- Dodecyl creatine ester (DCE) is the drug candidate currently being developed by Ceres Brain Therapeutics company.

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