Proteomes of human brain organoids derived from individuals with creatine transporter deficiency
Ontology highlight
ABSTRACT:
INSTRUMENT(S):
ORGANISM(S): Homo Sapiens (human)
TISSUE(S): Stem Cell
DISEASE(S): Creatine Transporter Deficiency
SUBMITTER: 
Jean ARMENGAUD
LAB HEAD: Jean Armengaud
PROVIDER: PXD040185 | Pride | 2023-10-12
REPOSITORIES: Pride
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| F228848.dat | Other | |||
| F228848.mzid.gz | Mzid | |||
| F228849.dat | Other | |||
| F228849.mzid.gz | Mzid | |||
| F228850.dat | Other |
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Project description:Mutations in the solute carrier family 6-member 8 (Slc6a8) gene, encoding the protein responsible for cellular creatine (Cr) uptake, cause Creatine Transporter Deficiency (CTD), an X-linked neurometabolic disorder presenting with intellectual disability, autistic-like features, and epilepsy. The pathological determinants of CTD are still poorly understood, hindering the development of therapies. In this study, we generated an extensive transcriptomic profile of CTD showing that Cr deficiency causes perturbations of gene expression in excitatory neurons, inhibitory cells, and oligodendrocytes which result in remodeling of circuit excitability and synaptic wiring. We also identified specific alterations of parvalbumin-expressing (PV+) interneurons, exhibiting a reduction in cellular and synaptic density, and a hypofunctional electrophysiological phenotype. Mice lacking Slc6a8 only in PV+ interneurons recapitulated numerous CTD features, including cognitive deterioration, impaired cortical processing and hyperexcitability of brain circuits, demonstrating that Cr deficit in PV+ interneurons is sufficient to determine the neurological phenotype of CTD. Moreover, a pharmacological treatment targeted to restore the efficiency of PV+ synapses significantly improved cortical activity in Slc6a8 knock-out animals. Altogether, these data demonstrate that Slc6a8 is critical for the normal function of PV+ interneurons and that impairment of these cells is central in the disease pathogenesis, suggesting a novel therapeutic venue for CTD.
2023-03-14 | GSE216766 | GEO
Project description:Mutations in the X-linked solute carrier family 6-member (Slc6a8) gene, encoding the protein responsible for cellular creatine (Cr) uptake, cause Creatine Transporter Deficiency (CTD), an X-linked neurometabolic disorder presenting with cognitive dysfunction, autistic-like features, and epilepsy. The pathological determinants of CTD are still poorly understood and this lack of knowledge might hinder the development of therapeutic strategies. Here, we show that Cr deficiency perturbs gene expression in excitatory neurons, inhibitory cells and oligodendrocytes, inducing a remodeling of circuit excitability and synaptic wiring, while no effects are present in astrocytes and endothelial cells. We also describe specific alterations of high-energy demanding, Parvalbumin-expressing (PV+) interneurons, exhibiting a reduction in cellular and synaptic density, and a hypofunctional phenotype, affecting initiation, kinetics and frequency of action potentials. Mice lacking Slc6a8 only in PV+ neurons recapitulate numerous CTD features, such as cognitive deterioration, impaired cortical processing and hyperexcitability of brain circuits, demonstrating that Cr deficit in PV+ cells is sufficient to determine the CTD neurological endophenotype. Moreover, a pharmacological treatment targeted to restore the efficiency of PV+ synapses induces a significant improvement of cortical activity in Slc6a8 knock-out animals. Altogether, these data establish that Slc6a8 is critical for the normal function of PV+ interneurons and that a subtle dysfunction of these cells is critical for the disease pathogenesis, suggesting a novel therapeutic venue for CTD.
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Project description:X-linked creatine transporter deficiency (CTD) is one of the three types of cerebral creatine deficiency disorders. CTD arises from pathogenic variants in the X-linked gene SLC6A8. We report the first phosphorus (31 P) MRS study of patients with CTD, where both phosphocreatine and total creatine concentrations were found to be markedly reduced. Despite the diminished role of creatine and phosphocreatine in oxidative phosphorylation in CTD, we found no elevation of lactate or lowered pH, indicating that the brain energy supply still largely relied on oxidative metabolism. Our results suggest that mitochondrial function is a potential therapeutic target for CTD.
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Project description:Creatine transporter deficiency (CTD) is an X-linked disease caused by mutations in the SLC6A8 gene. The impaired creatine uptake in the brain results in intellectual disability, behavioral disorders, language delay, and seizures. In this work, we generated human brain organoids from induced pluripotent stem cells of healthy subjects and CTD patients. Brain organoids from CTD donors had reduced creatine uptake compared with those from healthy donors. The expression of neural progenitor cell markers SOX2 and PAX6 was reduced in CTD-derived organoids, while GSK3β, a key regulator of neurogenesis, was up-regulated. Shotgun proteomics combined with integrative bioinformatic and statistical analysis identified changes in the abundance of proteins associated with intellectual disability, epilepsy, and autism. Re-establishment of the expression of a functional SLC6A8 in CTD-derived organoids restored creatine uptake and normalized the expression of SOX2, GSK3β, and other key proteins associated with clinical features of CTD patients. Our brain organoid model opens new avenues for further characterizing the CTD pathophysiology and supports the concept that reinstating creatine levels in patients with CTD could result in therapeutic efficacy.
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Project description:Creatine is an essential metabolite for the storage and rapid supply of energy in muscle and nerve cells. In humans, the creatine deficiency syndrome (CDS) is manifested by impaired metabolism, transport, and distribution of creatine throughout the body leading to severe forms of mental disabilities. One of the common cause of CDS is mutations that impact the function of the creatine transporter (SLC6A8). This study characterized 30 missense variants of SLC6A8, which include 15 variants of unknown significance and two which were not reported before. These variants were expressed in HEK293 cells, and their subcellular localization and transport activity was assessed. Further, for the first time the interactome of SLC6A8 WT was characterized by quantitative interaction proteomics. Computational methods were then used to first assess the impact of mutations upon the thermodynamic stability of SLC6A8. This was expanded by modeling the impact of mutations upon the inward and outward facing transporter conformation. Next, identified SLC6A8 protein interactions binary complexes were modelled and used to characterize the impact of variants upon the thermodynamic stability of the complexes. This was followed up, by performing for a subset of the variants the interaction proteomics analysis to study changes upon the identified SLC6A8 WT interactome.
2024-01-03 | PXD047111 | Pride
Project description:We sought to investigate the mechanisms of CrT modulation by saturating extracellular Cr. For this purpose, we used an in vitro system of 3T3 fibroblasts stably overexpressing CrT and followed a global gene array approach to test the hypothesis that saturating intracellular [Cr] increases the expression of candidate molecules that inhibit CrT activity. In this way, we would elucidate mechanisms of redox regulation in cases of fluctuating energy demands. 3T3-CrT cells were grown on 6-well plates to 70% confluency. n=3 replicate wells were treated with 5mM creatine monohydrate in growth media and n=3 wells remained untreated (controls).
2012-12-07 | E-GEOD-42356 | biostudies-arrayexpress
Project description:We report the first X-linked creatine-deficiency syndrome caused by a defective creatine transporter. The male index patient presented with developmental delay and hypotonia. Proton magnetic-resonance spectroscopy of his brain revealed absence of the creatine signal. However, creatine in urine and plasma was increased, and guanidinoacetate levels were normal. In three female relatives of the index patient, mild biochemical abnormalities and learning disabilities were present, to various extents. Fibroblasts from the index patient contained a hemizygous nonsense mutation in the gene SLC6A8 and were defective in creatine uptake. The three female relatives were heterozygous for this mutation in SLC6A8, which has been mapped to Xq28.
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Project description:BackgroundCreatine transporter deficiency (CTD) is a rare X-linked disorder of creatine transport caused by pathogenic variants in SLC6A8 (Xq28). The disorder is marked by developmental delay, especially speech delay. The biomarkers Aβ40, Aβ42 and total tau are abnormal in Alzheimer disease (AD), a common neurodegenerative disorder pathologically characterized by Aβ peptide containing amyloid plaques and tau neurofibrillary tangles. Although CTD results in neuronal energy deficiency, the pathological processes underlying the CTD phenotype are not fully characterized.MethodsCerebral spinal fluid (CSF) was collected as an optional part of a natural history study of CTD. Aβ40, Aβ42 and total tau levels were quantified in CSF from individuals with CTD and from age-appropriate comparison samples. Neuro3-Plex enzyme-linked immunoassay was performed on a Quanterix SR-X instrument. The Vineland Adaptive Behavior Scale, 3rd Edition was used to determine an overall Adaptive Behavior Composite (ABC) standard score.ResultsCSF from 12 individuals with CTD and 23 age appropriate non-CTD comparison samples were analyzed. We found that levels of total tau [t(32) = 4.05, p = 0.0003], Aβ40 [t(31) = 6.11, p < 0.0001], and Aβ42 [t(32) = 3.20, p = 0.003] were elevated in the participants with CTD relative to the comparison group. Additionally, except for one individual that we considered an outlier, all three biomarkers correlated inversely with the adaptive behavior score (total tau: ρ = -0.60 [-0.88, 0.005]; Aβ40: ρ = -0.67 [-0.91, -0.12]; Aβ42: ρ = -0.62 [-0.89, -0.02]).ConclusionWe describe here the novel finding of elevated protein biomarkers in the CSF of individuals with CTD. Aβ40, Aβ42 and total tau are markedly elevated in individuals with CTD compared to comparison samples, and increased levels of these biomarkers inversely correlated with ABC scores. We hypothesize that elevated CSF levels of Aβ40 and Aβ42 are due to cellular energy deficiency. Elevated CSF total tau levels may indicate ongoing neuronal damage. The observed inverse correlation of Vineland ABC scores with increased biomarker levels needs to be confirmed in a larger CTD cohort; however, our observation of increased Aβ40, Aβ42 and total tau levels in CSF from individuals with CTD may provide insight into pathological mechanisms contributing to the CTD phenotype and may prove useful as supportive data in future therapeutic trials.
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Project description:X-linked cerebral creatine deficiency (MIM 300036) is caused by deficiency of the creatine transporter encoded by the SLC6A8 gene. Here we report three patients with this condition from Israel. These unrelated patients were evaluated for global developmental delays and language apraxia. Borderline microcephaly was noted in one of them. Diagnosis was prompted by brain magnetic resonance imaging and spectroscopy which revealed normal white matter distribution, but absence of the creatine peak in all three patients. Biochemical testing indicated normal plasma levels of creatine and guanidinoacetate, but an increased urine creatine/creatinine ratio. The diagnosis was confirmed by demonstrating absent ([14])C-creatine transport in fibroblasts. Molecular studies indicated that the first patient is hemizygous for a single nucleotide change substituting a single amino acid (c.619 C > T, p.R207W). Expression studies in HeLa cells confirmed the causative role of the R207W substitution. The second patient had a three base pair deletion in the SLC6A8 gene (c.1222_1224delTTC, p.F408del) as well as a single base change (c.1254 + 1G > A) at a splicing site in the intron-exon junction of exon 8, the latter occurring de novo. The third patient, had a three base pair deletion (c.1006_1008delAAC, p.N336del) previously reported in other patients with creatine transporter deficiency. These three patients are the first reported cases of creatine transporter deficiency in Israel.
| S-EPMC4932609 | biostudies-literature