Mutant huntingtin impairs neurodevelopment in brain organoids
2024
Heinrich Heine University, Düsseldorf, Germany(1)
Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany(2)
Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany(2)
Huntington’s disease (HD) is caused by the expansion of the glutamine tract (poly-Q) in the protein huntingtin (HTT). This study investigated how the mutant HTT (mHTT) affects early human brain development using brain organoids derived from genetically engineered induced pluripotent stem cells (iPSCs) with inserted or removed poly-Q in the HTT gene. It was observed that mHTT disrupts neural progenitor organization and impairs the development of cerebral organoids. RNA sequencing and proteomic analyses identified CHCHD2 as a key dysregulated transcription factor in the mHTT condition, leading to abnormal mitochondrial morpho-dynamics. Overexpression of CHCHD2 reverted mitochondrial dysregulartion, and removing the poly-Q tract was able to normalize CHCHD2 levels, correcting mitochondrial defects. These findings suggest that mHTT-induced neurodevelopmental defects are closely linked to mitochondrial dysfunction, and that CHCHD2 could be a potential therapeutic target for early intervention in HD.
Mutant huntingtin impairs neurodevelopment in human brain organoids through CHCHD2-mediated neurometabolic failure
Alessandro Prigione(1), Jakob J. Metzger(2)
Added on: 03-24-2025
[1] https://www.nature.com/articles/s41467-024-51216-w
