Mutant huntingtin impairs neurodevelopment in human brain organoids through CHCHD2-mediated neurometabolic failure PMID: 39174523

RQC and Longevity Regulation

2026-09-03

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

Nat Commun. 2024 Aug 22;15(1):7027. doi: 10.1038/s41467-024-51216-w.

Pawel Lisowski ^# ¹ ² ³ ⁴ , Selene Lickfett ^# ⁵ ⁶ ⁷ , Agnieszka Rybak-Wolf ² ⁸ , Carmen Menacho ⁵ ⁶ , Stephanie Le ⁵ ⁶ , Tancredi Massimo Pentimalli ² ⁹ ¹⁰ , Sofia Notopoulou ¹¹ , Werner Dykstra ² ¹² , Daniel Oehler ¹³ , Sandra López-Calcerrada ¹⁴ , Barbara Mlody ² ¹⁵ , Maximilian Otto ¹ ² , Haijia Wu ¹⁶ , Yasmin Richter ¹⁷ , Philipp Roth ¹ ² , Ruchika Anand ¹⁸ , Linda A M Kulka ¹⁹ , David Meierhofer ²⁰ , Petar Glazar ² ⁹ ²⁰ , Ivano Legnini ² ⁹ ²¹ , Narasimha Swamy Telugu ² , Tobias Hahn ² , Nancy Neuendorf ² , Duncan C Miller ² , Annett Böddrich ² , Amin Polzin ¹³ , Ertan Mayatepek ⁶ , Sebastian Diecke ² ²² , Heidi Olzscha ¹⁶ ¹⁹ , Janine Kirstein ¹⁷ ²³ , Cristina Ugalde ¹⁴ ²⁴ ²⁵ , Spyros Petrakis ¹¹ , Sidney Cambridge ⁷ ²⁶ , Nikolaus Rajewsky ² ⁹ ²² ²⁷ ²⁸ ²⁹ , Ralf Kühn ² , Erich E Wanker ² , Josef Priller ³ ²⁹ ³⁰ ³¹ , Jakob J Metzger ³² ³³ , Alessandro Prigione ³⁴ ³⁵

Affiliations

1. Quantitative Stem Cell Biology, Berlin Institute for Medical Systems Biology (BIMSB), Berlin, Germany.
2. Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany.
3. Department of Psychiatry and Psychotherapy, Neuropsychiatry and Laboratory of Molecular Psychiatry, Charité - Universitätsmedizin, Berlin, Germany.
4. Department of Molecular Biology, Institute of Genetics and Animal Biotechnology, Polish Academy of Sciences, Jastrzebiec n/Warsaw, Poland.
5. Faculty of Mathematics and Natural Sciences, Heinrich Heine University, Düsseldorf, Germany.
6. Department of General Pediatrics, Neonatology and Pediatric Cardiology, Medical Faculty, University Hospital Düsseldorf, Heinrich Heine University, Düsseldorf, Germany.
7. Institute of Anatomy II, Heinrich-Heine-University, Düsseldorf, Germany.
8. Organoid Platform, Berlin Institute for Medical Systems Biology (BIMSB), Berlin, Germany.
9. Laboratory for Systems Biology of Gene Regulatory Elements, Berlin Institute for Medical Systems Biology (BIMSB), Berlin, Germany.
10. Charité - Universitätsmedizin, Berlin, Germany.
11. Institute of Applied Biosciences (INAB), Centre For Research and Technology Hellas (CERTH), Thessaloniki, Greece.
12. Department of Translational Neuroscience, University Medical Center Utrecht Brain Center, Utrecht, The Netherlands.
13. Division of Cardiology, Pulmonology, and Vascular Medicine, Medical Faculty and University Hospital Düsseldorf, Cardiovascular Research Institute Düsseldorf (CARID), Düsseldorf, Germany.
14. Instituto de Investigación Hospital 12 de Octubre (i + 12), Madrid, Spain.
15. Centogene, Rostock, Germany.
16. Institute of Molecular Medicine, Medical School, Hamburg, Germany.
17. Cell Biology, University of Bremen, Bremen, Germany.
18. Institute of Biochemistry and Molecular Biology I, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University, Düsseldorf, Germany.
19. Institute of Physiological Chemistry, Martin-Luther-University, Halle-Wittenberg, Germany.
20. Quantitative RNA Biology, Max Planck Institute for Molecular Genetics, Berlin, Germany.
21. Human Technopole, Milan, Italy.
22. German Center for Cardiovascular Research (DZHK), Berlin, Germany.
23. Leibniz Institute on Aging - Fritz-Lipmann Institute, Jena, Germany.
24. Centro de Investigaciones Biológicas Margarita Salas (CIB-CSIC), Madrid, Spain.
25. Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.
26. Dr. Senckenberg Anatomy, Anatomy II, Goethe-University, Frankfurt, Germany.
27. NeuroCure Cluster of Excellence, Berlin, Germany.
28. National Center for Tumor Diseases (NCT), German Cancer Consortium (DKTK), Berlin, Germany.
29. German Center for Neurodegenerative Diseases (DZNE), Berlin, Germany.
30. Department of Psychiatry and Psychotherapy; School of Medicine and Health, Technical University of Munich and German Center for Mental Health (DZPG), Munich, Germany.
31. University of Edinburgh and UK Dementia Research Institute, Edinburgh, UK.
32. Quantitative Stem Cell Biology, Berlin Institute for Medical Systems Biology (BIMSB), Berlin, Germany. [email protected].
33. Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany. [email protected].
34. Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany. [email protected].
35. Department of General Pediatrics, Neonatology and Pediatric Cardiology, Medical Faculty, University Hospital Düsseldorf, Heinrich Heine University, Düsseldorf, Germany. [email protected].
# Contributed equally.

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.