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

• DOI: 10.1038/s41467-024-51216-w
• Publication Date: 2024-08-23T13:50:40Z
• Authors: Pawel Lisowski; Selene Lickfett; Agnieszka Rybak-Wolf; Carmen Menacho; Stephanie Le; Tancredi Massimo ...; Sofia Notopoulou; Werner Dykstra; Daniel Oehler; Sandra López-Calc...; Barbara Mlody; Maximilian Otto; Haijia Wu; Yasmin Richter; Philipp Roth; Ruchika Anand; Linda A. M. Kulka; David Meierhofer; Petar Glazar; Ivano Legnini; Narasimha Swamy T...; 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; Alessandro Prigione
• Keywords: Huntingtin Protein

Abstract Expansion of the glutamine tract (poly-Q) in protein huntingtin (HTT) causes neurodegenerative disorder Huntington’s disease (HD). Emerging evidence suggests that mutant HTT (mHTT) disrupts brain development. To gain mechanistic insights into neurodevelopmental impact human mHTT, we engineered male induced pluripotent stem cells to introduce a biallelic or monoallelic 70Q expansion remove poly-Q HTT. The introduction mutation caused aberrant development cerebral organoids with loss neural progenitor organization. early signature mHTT highlighted dysregulation coiled-coil-helix-coiled-coil-helix domain containing 2 (CHCHD2), transcription factor involved mitochondrial integrated stress response. CHCHD2 repression was associated abnormal morpho-dynamics reverted upon overexpression CHCHD2. Removing from normalized levels and corrected key defects. Hence, mHTT-mediated disruption neurodevelopment is paralleled by neurometabolic programming mediated CHCHD2, which could then serve as an interventional target for HD.