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

Author

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  • Pawel Lisowski

    (Berlin Institute for Medical Systems Biology (BIMSB)
    Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC)
    Neuropsychiatry and Laboratory of Molecular Psychiatry, Charité – Universitätsmedizin
    Institute of Genetics and Animal Biotechnology, Polish Academy of Sciences)

  • Selene Lickfett

    (Heinrich Heine University
    Medical Faculty, University Hospital Düsseldorf, Heinrich Heine University
    Heinrich-Heine-University)

  • Agnieszka Rybak-Wolf

    (Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC)
    Berlin Institute for Medical Systems Biology (BIMSB))

  • Carmen Menacho

    (Heinrich Heine University
    Medical Faculty, University Hospital Düsseldorf, Heinrich Heine University)

  • Stephanie Le

    (Heinrich Heine University
    Medical Faculty, University Hospital Düsseldorf, Heinrich Heine University)

  • Tancredi Massimo Pentimalli

    (Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC)
    Berlin Institute for Medical Systems Biology (BIMSB)
    Charité – Universitätsmedizin)

  • Sofia Notopoulou

    (Centre For Research and Technology Hellas (CERTH))

  • Werner Dykstra

    (Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC)
    University Medical Center Utrecht Brain Center)

  • Daniel Oehler

    (Medical Faculty and University Hospital Düsseldorf, Cardiovascular Research Institute Düsseldorf (CARID))

  • Sandra López-Calcerrada

    (Instituto de Investigación Hospital 12 de Octubre (i + 12))

  • Barbara Mlody

    (Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC)
    Centogene)

  • Maximilian Otto

    (Berlin Institute for Medical Systems Biology (BIMSB)
    Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC))

  • Haijia Wu

    (Medical School)

  • Yasmin Richter

    (University of Bremen)

  • Philipp Roth

    (Berlin Institute for Medical Systems Biology (BIMSB)
    Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC))

  • Ruchika Anand

    (Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University)

  • Linda A. M. Kulka

    (Martin-Luther-University)

  • David Meierhofer

    (Max Planck Institute for Molecular Genetics)

  • Petar Glazar

    (Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC)
    Berlin Institute for Medical Systems Biology (BIMSB)
    Max Planck Institute for Molecular Genetics)

  • Ivano Legnini

    (Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC)
    Berlin Institute for Medical Systems Biology (BIMSB)
    Human Technopole)

  • Narasimha Swamy Telugu

    (Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC))

  • Tobias Hahn

    (Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC))

  • Nancy Neuendorf

    (Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC))

  • Duncan C. Miller

    (Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC))

  • Annett Böddrich

    (Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC))

  • Amin Polzin

    (Medical Faculty and University Hospital Düsseldorf, Cardiovascular Research Institute Düsseldorf (CARID))

  • Ertan Mayatepek

    (Medical Faculty, University Hospital Düsseldorf, Heinrich Heine University)

  • Sebastian Diecke

    (Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC)
    German Center for Cardiovascular Research (DZHK))

  • Heidi Olzscha

    (Medical School
    Martin-Luther-University)

  • Janine Kirstein

    (University of Bremen
    Leibniz Institute on Aging – Fritz-Lipmann Institute)

  • Cristina Ugalde

    (Instituto de Investigación Hospital 12 de Octubre (i + 12)
    Centro de Investigaciones Biológicas Margarita Salas (CIB-CSIC)
    Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER))

  • Spyros Petrakis

    (Centre For Research and Technology Hellas (CERTH))

  • Sidney Cambridge

    (Heinrich-Heine-University
    Anatomy II, Goethe-University)

  • Nikolaus Rajewsky

    (Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC)
    Berlin Institute for Medical Systems Biology (BIMSB)
    German Center for Cardiovascular Research (DZHK)
    NeuroCure Cluster of Excellence)

  • Ralf Kühn

    (Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC))

  • Erich E. Wanker

    (Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC))

  • Josef Priller

    (Neuropsychiatry and Laboratory of Molecular Psychiatry, Charité – Universitätsmedizin
    German Center for Neurodegenerative Diseases (DZNE)
    Technical University of Munich and German Center for Mental Health (DZPG)
    University of Edinburgh and UK Dementia Research Institute)

  • Jakob J. Metzger

    (Berlin Institute for Medical Systems Biology (BIMSB)
    Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC))

  • Alessandro Prigione

    (Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC)
    Medical Faculty, University Hospital Düsseldorf, Heinrich Heine University)

Abstract

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.

Suggested Citation

  • Pawel Lisowski & Selene Lickfett & Agnieszka Rybak-Wolf & Carmen Menacho & Stephanie Le & Tancredi Massimo Pentimalli & Sofia Notopoulou & Werner Dykstra & Daniel Oehler & Sandra López-Calcerrada & Ba, 2024. "Mutant huntingtin impairs neurodevelopment in human brain organoids through CHCHD2-mediated neurometabolic failure," Nature Communications, Nature, vol. 15(1), pages 1-27, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-51216-w
    DOI: 10.1038/s41467-024-51216-w
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    References listed on IDEAS

    as
    1. Margarete Diaz-Cuadros & Teemu P. Miettinen & Owen S. Skinner & Dylan Sheedy & Carlos Manlio Díaz-García & Svetlana Gapon & Alexis Hubaud & Gary Yellen & Scott R. Manalis & William M. Oldham & Olivier, 2023. "Metabolic regulation of species-specific developmental rates," Nature, Nature, vol. 613(7944), pages 550-557, January.
    2. Margarete Diaz-Cuadros & Teemu P. Miettinen & Owen S. Skinner & Dylan Sheedy & Carlos Manlio Díaz-García & Svetlana Gapon & Alexis Hubaud & Gary Yellen & Scott R. Manalis & William M. Oldham & Olivier, 2023. "Author Correction: Metabolic regulation of species-specific developmental rates," Nature, Nature, vol. 616(7956), pages 4-4, April.
    3. Florian Krach & Judith Stemick & Tom Boerstler & Alexander Weiss & Ioannis Lingos & Stephanie Reischl & Holger Meixner & Sonja Ploetz & Michaela Farrell & Ute Hehr & Zacharias Kohl & Beate Winner & Ju, 2022. "An alternative splicing modulator decreases mutant HTT and improves the molecular fingerprint in Huntington’s disease patient neurons," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
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