Deciphering neuronal deficit and protein profile changes in human brain organoids from patients with creatine transporter deficiency
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 pluripo...
| Main Authors: | , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
eLife Sciences Publications Ltd
2023-10-01
|
| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/88459 |
| _version_ | 1797660410855292928 |
|---|---|
| author | Léa Broca-Brisson Rania Harati Clémence Disdier Orsolya Mozner Romane Gaston-Breton Auriane Maïza Narciso Costa Anne-Cécile Guyot Balazs Sarkadi Agota Apati Matthew R Skelton Lucie Madrange Frank Yates Jean Armengaud Rifat Hamoudi Aloïse Mabondzo |
| author_facet | Léa Broca-Brisson Rania Harati Clémence Disdier Orsolya Mozner Romane Gaston-Breton Auriane Maïza Narciso Costa Anne-Cécile Guyot Balazs Sarkadi Agota Apati Matthew R Skelton Lucie Madrange Frank Yates Jean Armengaud Rifat Hamoudi Aloïse Mabondzo |
| author_sort | Léa Broca-Brisson |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-03-11T18:30:27Z |
| format | Article |
| id | doaj.art-e52897c931c1438dbf89ad9807783b44 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-03-11T18:30:27Z |
| publishDate | 2023-10-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-e52897c931c1438dbf89ad9807783b442023-10-13T13:31:00ZengeLife Sciences Publications LtdeLife2050-084X2023-10-011210.7554/eLife.88459Deciphering neuronal deficit and protein profile changes in human brain organoids from patients with creatine transporter deficiencyLéa Broca-Brisson0Rania Harati1Clémence Disdier2Orsolya Mozner3https://orcid.org/0000-0001-5784-7702Romane Gaston-Breton4Auriane Maïza5Narciso Costa6Anne-Cécile Guyot7Balazs Sarkadi8https://orcid.org/0000-0003-0592-4539Agota Apati9https://orcid.org/0000-0003-0380-8139Matthew R Skelton10Lucie Madrange11Frank Yates12Jean Armengaud13https://orcid.org/0000-0003-1589-445XRifat Hamoudi14Aloïse Mabondzo15https://orcid.org/0000-0002-0627-8949Université Paris-Saclay, CEA, INRAE, Département Médicaments et Technologies pour la Santé, Gif sur Yvette, FranceDepartment of Pharmacy Practice and Pharmacotherapeutics, College of Pharmacy, University of Sharjah, Sharjah, United Arab Emirates; Sharjah Institute for Medical Research, University of Sharjah, Sharjah, United Arab EmiratesCERES BRAIN Therapeutics, Paris, FranceInstitute of Enzymology, Research Centre for Natural Sciences, ELKH, and Doctoral School of Molecular Medicine, Semmelweis University, Budapest, HungaryUniversité Paris-Saclay, CEA, INRAE, Département Médicaments et Technologies pour la Santé, Gif sur Yvette, FranceUniversité Paris-Saclay, CEA, INRAE, Département Médicaments et Technologies pour la Santé, Gif sur Yvette, FranceUniversité Paris-Saclay, CEA, INRAE, Département Médicaments et Technologies pour la Santé, Gif sur Yvette, FranceUniversité Paris-Saclay, CEA, INRAE, Département Médicaments et Technologies pour la Santé, Gif sur Yvette, FranceInstitute of Enzymology, Research Centre for Natural Sciences, ELKH, and Doctoral School of Molecular Medicine, Semmelweis University, Budapest, HungaryInstitute of Enzymology, Research Centre for Natural Sciences, ELKH, and Doctoral School of Molecular Medicine, Semmelweis University, Budapest, HungaryDepartment of Pediatrics, University of Cincinnati College of Medicine and Division of Neurology, Cincinnati Children’s Research Foundation, Cincinnati, United StatesSupBiotech/Service d'Etude des Prions et des Infections Atypiques (SEPIA), Institut François Jacob, CEA, Université Paris Saclay, Paris, FranceSupBiotech/Service d'Etude des Prions et des Infections Atypiques (SEPIA), Institut François Jacob, CEA, Université Paris Saclay, Paris, FranceUniversité Paris-Saclay, CEA, INRAE, Département Médicaments et Technologies pour la Santé (DMTS), SPI, Bagnols-sur-Cèze, FranceClinical Sciences Department, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates; Division of Surgery and Interventional Science, University College London, London, United Kingdom; ASPIRE Precision Medicine Research Institute Abu Dhabi, University of Sharjah, Sharjah, United Arab EmiratesUniversité Paris-Saclay, CEA, INRAE, Département Médicaments et Technologies pour la Santé, Gif sur Yvette, FranceCreatine 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.https://elifesciences.org/articles/88459cortexbrainneurogenesis |
| spellingShingle | Léa Broca-Brisson Rania Harati Clémence Disdier Orsolya Mozner Romane Gaston-Breton Auriane Maïza Narciso Costa Anne-Cécile Guyot Balazs Sarkadi Agota Apati Matthew R Skelton Lucie Madrange Frank Yates Jean Armengaud Rifat Hamoudi Aloïse Mabondzo Deciphering neuronal deficit and protein profile changes in human brain organoids from patients with creatine transporter deficiency eLife cortex brain neurogenesis |
| title | Deciphering neuronal deficit and protein profile changes in human brain organoids from patients with creatine transporter deficiency |
| title_full | Deciphering neuronal deficit and protein profile changes in human brain organoids from patients with creatine transporter deficiency |
| title_fullStr | Deciphering neuronal deficit and protein profile changes in human brain organoids from patients with creatine transporter deficiency |
| title_full_unstemmed | Deciphering neuronal deficit and protein profile changes in human brain organoids from patients with creatine transporter deficiency |
| title_short | Deciphering neuronal deficit and protein profile changes in human brain organoids from patients with creatine transporter deficiency |
| title_sort | deciphering neuronal deficit and protein profile changes in human brain organoids from patients with creatine transporter deficiency |
| topic | cortex brain neurogenesis |
| url | https://elifesciences.org/articles/88459 |
| work_keys_str_mv | AT leabrocabrisson decipheringneuronaldeficitandproteinprofilechangesinhumanbrainorganoidsfrompatientswithcreatinetransporterdeficiency AT raniaharati decipheringneuronaldeficitandproteinprofilechangesinhumanbrainorganoidsfrompatientswithcreatinetransporterdeficiency AT clemencedisdier decipheringneuronaldeficitandproteinprofilechangesinhumanbrainorganoidsfrompatientswithcreatinetransporterdeficiency AT orsolyamozner decipheringneuronaldeficitandproteinprofilechangesinhumanbrainorganoidsfrompatientswithcreatinetransporterdeficiency AT romanegastonbreton decipheringneuronaldeficitandproteinprofilechangesinhumanbrainorganoidsfrompatientswithcreatinetransporterdeficiency AT aurianemaiza decipheringneuronaldeficitandproteinprofilechangesinhumanbrainorganoidsfrompatientswithcreatinetransporterdeficiency AT narcisocosta decipheringneuronaldeficitandproteinprofilechangesinhumanbrainorganoidsfrompatientswithcreatinetransporterdeficiency AT annececileguyot decipheringneuronaldeficitandproteinprofilechangesinhumanbrainorganoidsfrompatientswithcreatinetransporterdeficiency AT balazssarkadi decipheringneuronaldeficitandproteinprofilechangesinhumanbrainorganoidsfrompatientswithcreatinetransporterdeficiency AT agotaapati decipheringneuronaldeficitandproteinprofilechangesinhumanbrainorganoidsfrompatientswithcreatinetransporterdeficiency AT matthewrskelton decipheringneuronaldeficitandproteinprofilechangesinhumanbrainorganoidsfrompatientswithcreatinetransporterdeficiency AT luciemadrange decipheringneuronaldeficitandproteinprofilechangesinhumanbrainorganoidsfrompatientswithcreatinetransporterdeficiency AT frankyates decipheringneuronaldeficitandproteinprofilechangesinhumanbrainorganoidsfrompatientswithcreatinetransporterdeficiency AT jeanarmengaud decipheringneuronaldeficitandproteinprofilechangesinhumanbrainorganoidsfrompatientswithcreatinetransporterdeficiency AT rifathamoudi decipheringneuronaldeficitandproteinprofilechangesinhumanbrainorganoidsfrompatientswithcreatinetransporterdeficiency AT aloisemabondzo decipheringneuronaldeficitandproteinprofilechangesinhumanbrainorganoidsfrompatientswithcreatinetransporterdeficiency |