Mutant huntingtin impairs neurodevelopment in human brain organoids through CHCHD2-mediated neurometabolic failure.

Autor: Lisowski P; Quantitative Stem Cell Biology, Berlin Institute for Medical Systems Biology (BIMSB), Berlin, Germany.; Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany.; Department of Psychiatry and Psychotherapy, Neuropsychiatry and Laboratory of Molecular Psychiatry, Charité - Universitätsmedizin, Berlin, Germany.; Department of Molecular Biology, Institute of Genetics and Animal Biotechnology, Polish Academy of Sciences, Jastrzebiec n/Warsaw, Poland., Lickfett S; Faculty of Mathematics and Natural Sciences, Heinrich Heine University, Düsseldorf, Germany.; Department of General Pediatrics, Neonatology and Pediatric Cardiology, Medical Faculty, University Hospital Düsseldorf, Heinrich Heine University, Düsseldorf, Germany.; Institute of Anatomy II, Heinrich-Heine-University, Düsseldorf, Germany., Rybak-Wolf A; Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany.; Organoid Platform, Berlin Institute for Medical Systems Biology (BIMSB), Berlin, Germany., Menacho C; Faculty of Mathematics and Natural Sciences, Heinrich Heine University, Düsseldorf, Germany.; Department of General Pediatrics, Neonatology and Pediatric Cardiology, Medical Faculty, University Hospital Düsseldorf, Heinrich Heine University, Düsseldorf, Germany., Le S; Faculty of Mathematics and Natural Sciences, Heinrich Heine University, Düsseldorf, Germany.; Department of General Pediatrics, Neonatology and Pediatric Cardiology, Medical Faculty, University Hospital Düsseldorf, Heinrich Heine University, Düsseldorf, Germany., Pentimalli TM; Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany.; Laboratory for Systems Biology of Gene Regulatory Elements, Berlin Institute for Medical Systems Biology (BIMSB), Berlin, Germany.; Charité - Universitätsmedizin, Berlin, Germany., Notopoulou S; Institute of Applied Biosciences (INAB), Centre For Research and Technology Hellas (CERTH), Thessaloniki, Greece., Dykstra W; Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany.; Department of Translational Neuroscience, University Medical Center Utrecht Brain Center, Utrecht, The Netherlands., Oehler D; Division of Cardiology, Pulmonology, and Vascular Medicine, Medical Faculty and University Hospital Düsseldorf, Cardiovascular Research Institute Düsseldorf (CARID), Düsseldorf, Germany., López-Calcerrada S; Instituto de Investigación Hospital 12 de Octubre (i + 12), Madrid, Spain., Mlody B; Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany.; Centogene, Rostock, Germany., Otto M; Quantitative Stem Cell Biology, Berlin Institute for Medical Systems Biology (BIMSB), Berlin, Germany.; Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany., Wu H; Institute of Molecular Medicine, Medical School, Hamburg, Germany., Richter Y; Cell Biology, University of Bremen, Bremen, Germany., Roth P; Quantitative Stem Cell Biology, Berlin Institute for Medical Systems Biology (BIMSB), Berlin, Germany.; Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany., Anand R; Institute of Biochemistry and Molecular Biology I, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University, Düsseldorf, Germany., Kulka LAM; Institute of Physiological Chemistry, Martin-Luther-University, Halle-Wittenberg, Germany., Meierhofer D; Quantitative RNA Biology, Max Planck Institute for Molecular Genetics, Berlin, Germany., Glazar P; Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany.; Laboratory for Systems Biology of Gene Regulatory Elements, Berlin Institute for Medical Systems Biology (BIMSB), Berlin, Germany.; Quantitative RNA Biology, Max Planck Institute for Molecular Genetics, Berlin, Germany., Legnini I; Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany.; Laboratory for Systems Biology of Gene Regulatory Elements, Berlin Institute for Medical Systems Biology (BIMSB), Berlin, Germany.; Human Technopole, Milan, Italy., Telugu NS; Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany., Hahn T; Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany., Neuendorf N; Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany., Miller DC; Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany., Böddrich A; Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany., Polzin A; Division of Cardiology, Pulmonology, and Vascular Medicine, Medical Faculty and University Hospital Düsseldorf, Cardiovascular Research Institute Düsseldorf (CARID), Düsseldorf, Germany., Mayatepek E; Department of General Pediatrics, Neonatology and Pediatric Cardiology, Medical Faculty, University Hospital Düsseldorf, Heinrich Heine University, Düsseldorf, Germany., Diecke S; Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany.; German Center for Cardiovascular Research (DZHK), Berlin, Germany., Olzscha H; Institute of Molecular Medicine, Medical School, Hamburg, Germany.; Institute of Physiological Chemistry, Martin-Luther-University, Halle-Wittenberg, Germany., Kirstein J; Cell Biology, University of Bremen, Bremen, Germany.; Leibniz Institute on Aging - Fritz-Lipmann Institute, Jena, Germany., Ugalde C; Instituto de Investigación Hospital 12 de Octubre (i + 12), Madrid, Spain.; Centro de Investigaciones Biológicas Margarita Salas (CIB-CSIC), Madrid, Spain.; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain., Petrakis S; Institute of Applied Biosciences (INAB), Centre For Research and Technology Hellas (CERTH), Thessaloniki, Greece., Cambridge S; Institute of Anatomy II, Heinrich-Heine-University, Düsseldorf, Germany.; Dr. Senckenberg Anatomy, Anatomy II, Goethe-University, Frankfurt, Germany., Rajewsky N; Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany.; Laboratory for Systems Biology of Gene Regulatory Elements, Berlin Institute for Medical Systems Biology (BIMSB), Berlin, Germany.; German Center for Cardiovascular Research (DZHK), Berlin, Germany.; NeuroCure Cluster of Excellence, Berlin, Germany.; National Center for Tumor Diseases (NCT), German Cancer Consortium (DKTK), Berlin, Germany.; German Center for Neurodegenerative Diseases (DZNE), Berlin, Germany., Kühn R; Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany., Wanker EE; Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany., Priller J; Department of Psychiatry and Psychotherapy, Neuropsychiatry and Laboratory of Molecular Psychiatry, Charité - Universitätsmedizin, Berlin, Germany.; German Center for Neurodegenerative Diseases (DZNE), Berlin, Germany.; Department of Psychiatry and Psychotherapy; School of Medicine and Health, Technical University of Munich and German Center for Mental Health (DZPG), Munich, Germany.; University of Edinburgh and UK Dementia Research Institute, Edinburgh, UK., Metzger JJ; Quantitative Stem Cell Biology, Berlin Institute for Medical Systems Biology (BIMSB), Berlin, Germany. jakob.metzger@mdc-berlin.de.; Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany. jakob.metzger@mdc-berlin.de., Prigione A; Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany. alessandro.prigione@hhu.de.; Department of General Pediatrics, Neonatology and Pediatric Cardiology, Medical Faculty, University Hospital Düsseldorf, Heinrich Heine University, Düsseldorf, Germany. alessandro.prigione@hhu.de.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2024 Aug 22; Vol. 15 (1), pp. 7027. Date of Electronic Publication: 2024 Aug 22.
DOI: 10.1038/s41467-024-51216-w
Abstrakt: Expansion of the glutamine tract (poly-Q) in the protein huntingtin (HTT) causes the neurodegenerative disorder Huntington's disease (HD). Emerging evidence suggests that mutant HTT (mHTT) disrupts brain development. To gain mechanistic insights into the neurodevelopmental impact of human mHTT, we engineered male induced pluripotent stem cells to introduce a biallelic or monoallelic mutant 70Q expansion or to remove the poly-Q tract of HTT. The introduction of a 70Q mutation caused aberrant development of cerebral organoids with loss of neural progenitor organization. The early neurodevelopmental signature of mHTT highlighted the dysregulation of the protein coiled-coil-helix-coiled-coil-helix domain containing 2 (CHCHD2), a transcription factor involved in mitochondrial integrated stress response. CHCHD2 repression was associated with abnormal mitochondrial morpho-dynamics that was reverted upon overexpression of CHCHD2. Removing the poly-Q tract from HTT normalized CHCHD2 levels and corrected key mitochondrial defects. Hence, mHTT-mediated disruption of human neurodevelopment is paralleled by aberrant neurometabolic programming mediated by dysregulation of CHCHD2, which could then serve as an early interventional target for HD.
(© 2024. The Author(s).)
Databáze: MEDLINE
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