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

Paweł Lisowski(Max Delbrück Center), Selene Lickfett(Heinrich Heine University Düsseldorf), Agnieszka Rybak‐Wolf(Max Delbrück Center), Stephanie Le(Heinrich Heine University Düsseldorf), Werner Dykstra(Max Delbrück Center), Barbara Mlody(Max Delbrück Center), Carmen Menacho(Heinrich Heine University Düsseldorf), Philipp von Roth(Max Delbrück Center), Yasmin Richter(University of Bremen), Linda Anna Michelle Kulka(Martin Luther University Halle-Wittenberg), Petar Glažar(Max Delbrück Center), Haijia Wu(Martin Luther University Halle-Wittenberg), David Meierhofer(Max Planck Institute for Molecular Genetics), Ivano Legnini(Max Delbrück Center), Max Otto(Max Delbrück Center), Duncan C. Miller(Max Delbrück Center), Nancy Neuendorf(Max Delbrück Center), Tobias Hahn(Max Delbrück Center), Narasimha Swamy Telugu(Max Delbrück Center), Annett Böddrich(Max Delbrück Center), Ertan Mayatepek(Heinrich Heine University Düsseldorf), Sebastian Diecke(Max Delbrück Center), Heidi Olzscha(MSH Medical School Hamburg – University of Applied Sciences and Medical University), Janine Kirstein(University of Bremen), Ralf Kühn(Max Delbrück Center), Sidney Cambridge(Goethe University Frankfurt), Nikolaus Rajewsky(Max Delbrück Center), Erich E. Wanker(Max Delbrück Center), Josef Priller(German Center for Neurodegenerative Diseases), Jakob J. Metzger(Max Delbrück Center), Alessandro Prigione(Max Delbrück Center)
bioRxiv (Cold Spring Harbor Laboratory)
June 4, 2023
10.1101/2023.06.03.543551
Cited by 4Open Access
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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 induced pluripotent stem cells to introduce a biallelic or monoallelic mutant 70Q expansion or to remove the poly-Q tract of HTT. 70Q introduction 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 and elevated resting energy expenditure. Elimination of the poly-Q tract of HTT normalized CHCHD2 expression and 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 intervention target for HD.

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