Deciphering Neuronal Deficit and Protein Profile Changes in Human Brain Organoids from Patients with Creatine Transporter Deficiency
Broca-Brisson, L.; Harati, R.; Disdier, C.; Mozner, O.; Gaston-Breton, R.; Maiza, A.; Costa, N.; Guyot, A.-C.; Sarkadi, B.; Apati, A.; Skelton, M.; Madrange, L.; Yates, F.; Armengaud, J.; Hamoudi, R. A.; Mabondzo, A.
Show abstract
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 GSK3{beta}, a key regulator of neurogenesis, was up-regulated. Shotgun proteomics combined with integrative bioinformatic and statistical analysis identified changes in abundance of proteins associated with intellectual disability, epilepsy, and autism. Re-establishment of the expression a functional SLC6A8 in CTD-derived organoids restored creatine uptake and normalized the expression of SOX2, GSK3{beta} 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. Summary HeadingTherapeutic targets associated with Creatine Transporter Deficiency
Matching journals
The top 11 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Cockayne syndrome patient iPSC-derived brain organoids and neurospheres show early transcriptional dysregulation of biological processes associated with brain development and metabolism. 96%
- Impaired p53-mediated DNA damage response contributes to microcephaly in Nijmegen Breakage Syndrome patient-derived cerebral organoids 95%
- Heterologous HSPC transplantation rescues neuroinflammation and ameliorates peripheral manifestations in the mouse model of lysosomal transmembrane enzyme deficiency, MPS IIIC. 93%
Similar papers in this journal
- Human neural rosettes secrete bioactive extracellular vesicles enriched in neuronal and glial cellular components 96%
- Human Cerebral Spheroids Undergo Activity Dependent Changes In Cellular Composition And MicroRNA Expression 95%
- GluN2A-mediated currents and calcium signal in human iPSC-derived neurons 95%
Similar papers in this journal
- Frontotemporal dementia patient-derived iPSC neurons show cell pathological hallmarks and evidence for synaptic dysfunction and DNA damage 96%
- Induced pluripotent stem cell-derived astrocytes from patients with schizophrenia exhibit an inflammatory phenotype that affects vascularization 96%
- Maternal Immune Activation imprints translational dysregulation and differential MAP2 phosphorylation in descendant neural stem cells 95%
Similar papers in this journal
- A human forebrain organoid model reveals the essential function of GTF2IRD1-TTR-ERK axis for the neurodevelopmental deficits of Williams Syndrome 96%
- The LRRK2 G2019S mutation alters astrocyte-to-neuron communication via extracellular vesicles and induces neuron atrophy in a human iPSC-derived model of Parkinson's disease 94%
- Olfactory ensheathing cells from adult female rats are hybrid glia that promote neural repair 93%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.