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

Pawel Lisowski, Selene Lickfett, Agnieszka Rybak-Wolf, Carmen Menacho, Stephanie Le, Tancredi Massimo Pentimalli, Sofia Notopoulou, Werner Dykstra, Daniel Oehler, Sandra López-Calcerrada, Barbara Mlody, Maximilian Otto, Haijia Wu, Yasmin Richter, Philipp Roth, Ruchika Anand, Linda A. M. Kulka, David Meierhofer, Petar Glazar, Ivano Legnini, Narasimha Swamy Telugu, Tobias Hahn, Nancy Neuendorf, Duncan C. Miller, Annett Böddrich, Amin Polzin, Ertan Mayatepek, Sebastian Diecke, Heidi Olzscha, Janine Kirstein, Cristina Ugalde, Spyros Petrakis, Sidney Cambridge, Nikolaus Rajewsky, Ralf Kühn, Erich E. Wanker, Josef Priller, Jakob J. Metzger () and Alessandro Prigione ()
Additional contact information
Pawel Lisowski: Berlin Institute for Medical Systems Biology (BIMSB)
Selene Lickfett: Heinrich Heine University
Agnieszka Rybak-Wolf: Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC)
Carmen Menacho: Heinrich Heine University
Stephanie Le: Heinrich Heine University
Tancredi Massimo Pentimalli: Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC)
Sofia Notopoulou: Centre For Research and Technology Hellas (CERTH)
Werner Dykstra: Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC)
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)
Maximilian Otto: Berlin Institute for Medical Systems Biology (BIMSB)
Haijia Wu: Medical School
Yasmin Richter: University of Bremen
Philipp Roth: Berlin Institute for Medical Systems Biology (BIMSB)
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)
Ivano Legnini: Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC)
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)
Heidi Olzscha: Medical School
Janine Kirstein: University of Bremen
Cristina Ugalde: Instituto de Investigación Hospital 12 de Octubre (i + 12)
Spyros Petrakis: Centre For Research and Technology Hellas (CERTH)
Sidney Cambridge: Heinrich-Heine-University
Nikolaus Rajewsky: Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC)
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
Jakob J. Metzger: Berlin Institute for Medical Systems Biology (BIMSB)
Alessandro Prigione: Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC)

Nature Communications, 2024, vol. 15, issue 1, 1-27

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-51216-w

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