1. Human iPSC-derived neurons reveal early developmental alteration of neurite outgrowth in the late-occurring neurodegenerative Wolfram syndrome
- Author
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Jérôme Polentes, Hélène Polvèche, Cécile Martinat, Axel Sciauvaud, Maria-Gabriela Boza-Moran, Laetitia Aubry, Marc Peschanski, Margot Jarrige, Sandra Pourtoy-Brasselet, Michel Cailleret, Eric Chevet, Institut des cellules souches pour le traitement et l'étude des maladies monogéniques (I-STEM), Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Généthon, CRLCC Eugène Marquis (CRLCC), Chemistry, Oncogenesis, Stress and Signaling (COSS), Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), I-Stem is part of the Biotherapies Institute for Rare Diseases (BIRD) supported by the Association Française contre les Myopathies (AFM-Téléthon). This project was also supported by grants from Association syndrome de Wolfram, Association Nationale de la Recherche et de la Technologie and Agence Nationale pour la Recherche : NeurATRIS ANR-11-INBS-0011 and Labex REVIVE ANR-10-LABX-73. M.-G.B.-M. was supported by the programme 'investissement d’avenir' INGESTEM. We thank Yolande Masson and Lina El Kassar for karyotyping the cell lines and Alexandre Carteron for the technical support with the ampliseq experiments. We thank Dr Cécile Delettre and the late Pr Christian Hamel (Institut des neurosciences de Montpellier) for the gift of the WS5 fibroblasts, and the New York Stem Cell Foundation for WS1 and WS2 iPSC lines. We thank Pr Ole Isacson (Harvard Medical School) for advice and reading the manuscript and Pr Nathalie Holic for advice with genome editing. We gratefully acknowledge support from the PSMN (Pôle Scientifique de Modélisation Numérique) of the ENS de Lyon for computing resource, ANR-11-INBS-0011,NeurATRIS,Infrastructure de Recherche Translationnelle pour les Biothérapies en Neurosciences(2011), ANR-10-LABX-0073,REVIVE,Stem Cells in Regenerative Biology and Medicine(2010), Institut National de la Santé et de la Recherche Médicale (INSERM)-CRLCC Eugène Marquis (CRLCC)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Aubry, Laetitia, Infrastructures - Infrastructure de Recherche Translationnelle pour les Biothérapies en Neurosciences - - NeurATRIS2011 - ANR-11-INBS-0011 - INBS - VALID, and Laboratoires d'excellence - Stem Cells in Regenerative Biology and Medicine - - REVIVE2010 - ANR-10-LABX-0073 - LABX - VALID
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neurite outgrowth ,Neurite ,induced pluripotent stem cells ,Wolfram syndrome ,[SDV]Life Sciences [q-bio] ,neurons ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Biology ,Article ,03 medical and health sciences ,neurodegenerative disease ,0302 clinical medicine ,[SDV.CAN] Life Sciences [q-bio]/Cancer ,Neurites ,Genetics ,medicine ,Humans ,Age of Onset ,Induced pluripotent stem cell ,Genetics (clinical) ,030304 developmental biology ,0303 health sciences ,Valproic Acid ,axon guidance ,Endoplasmic reticulum ,medicine.disease ,Phenotype ,[SDV] Life Sciences [q-bio] ,neurodevelopmental disease ,Gene Expression Regulation ,Case-Control Studies ,endoplasmic reticulum stress ,Unfolded protein response ,Axon guidance ,CRISPR-Cas Systems ,Neuroscience ,030217 neurology & neurosurgery ,medicine.drug - Abstract
International audience; Recent studies indicate that neurodegenerative processes that appear during childhood and adolescence in individuals with Wolfram syndrome (WS) occur in addition to early brain development alteration, which is clinically silent. Underlying pathological mechanisms are still unknown. We have used induced pluripotent stem cell-derived neural cells from individuals affected by WS in order to reveal their phenotypic and molecular correlates. We have observed that a subpopulation of Wolfram neurons displayed aberrant neurite outgrowth associated with altered expression of axon guidance genes. Selective inhibition of the ATF6α arm of the unfolded protein response prevented the altered phenotype, although acute endoplasmic reticulum stress response—which is activated in late Wolfram degenerative processes—was not detected. Among the drugs currently tried in individuals with WS, valproic acid was the one that prevented the pathological phenotypes. These results suggest that early defects in axon guidance may contribute to the loss of neurons in individuals with WS.
- Published
- 2021
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