التفاصيل البيبلوغرافية
| العنوان: |
Mutant huntingtin impairs neurodevelopment in human brain organoids through CHCHD2-mediated neurometabolic failure |
| المؤلفون: |
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, Alessandro Prigione |
| المصدر: |
Nature Communications, Vol 15, Iss 1, Pp 1-27 (2024) |
| بيانات النشر: |
Nature Portfolio, 2024. |
| سنة النشر: |
2024 |
| المجموعة: |
LCC:Science |
| مصطلحات موضوعية: |
Science |
| الوصف: |
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. |
| نوع الوثيقة: |
article |
| وصف الملف: |
electronic resource |
| اللغة: |
English |
| تدمد: |
2041-1723 |
| Relation: |
https://doaj.org/toc/2041-1723 |
| DOI: |
10.1038/s41467-024-51216-w |
| URL الوصول: |
https://doaj.org/article/340c015abcae4c679391b04ea77b6a41 |
| رقم الانضمام: |
edsdoj.340c015abcae4c679391b04ea77b6a41 |
| قاعدة البيانات: |
Directory of Open Access Journals |
Full Text Finder