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

Humans Transcription Factors / metabolism DNA-Binding Proteins / metabolism Huntingtin Protein / genetics Organoids / metabolism Mitochondrial Proteins / metabolism Brain / metabolism Huntington Disease / metabolism Induced Pluripotent Stem Cells / metabolism Male Mitochondria / metabolism Mutation Mitochondrial Dynamics / genetics

Journal

Nature communications

ISSN: 2041-1723

Titre abrégé: Nat Commun

Pays: England

ID NLM: 101528555

Informations de publication

Date de publication:
22 Aug 2024

Historique:

received: 03 06 2023

accepted: 01 08 2024

medline: 23 8 2024

pubmed: 23 8 2024

entrez: 22 8 2024

Statut: epublish

Résumé

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.

Identifiants

DOI: 10.1038/s41467-024-51216-w PMID: 39174523

pubmed: 39174523

doi: 10.1038/s41467-024-51216-w

pii: 10.1038/s41467-024-51216-w

doi:

Substances chimiques

CHCHD2 protein, human 0

Transcription Factors 0

DNA-Binding Proteins 0

Huntingtin Protein 0

Mitochondrial Proteins 0

HTT protein, human 0

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

Pagination

7027

Subventions

Organisme : Deutsche Forschungsgemeinschaft (German Research Foundation)

ID : PR1527/5-1

Organisme : Bundesministerium für Bildung und Forschung (Federal Ministry of Education and Research)

ID : 01GM2002A

Organisme : EC | EU Framework Programme for Research and Innovation H2020 | H2020 European Institute of Innovation and Technology (H2020 The European Institute of Innovation and Technology)

ID : 101080249

Informations de copyright

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