Mono- and Biallelic Inactivation of Huntingtin Gene in Patient-Specific Induced Pluripotent Stem Cells Reveal HTT Roles in Striatal Development and Neuronal Functions.

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State: Public
Version: Author's accepted manuscript
License: CC BY 4.0
Serval ID
serval:BIB_287CEF2B1872
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Mono- and Biallelic Inactivation of Huntingtin Gene in Patient-Specific Induced Pluripotent Stem Cells Reveal HTT Roles in Striatal Development and Neuronal Functions.
Journal
Journal of Huntington's disease
Author(s)
Louessard M., Cailleret M., Jarrige M., Bigarreau J., Lenoir S., Dufour N., Rey M., Saudou F., Deglon N., Perrier A.L.
ISSN
1879-6400 (Electronic)
ISSN-L
1879-6397
Publication state
Published
Issued date
2024
Peer-reviewed
Oui
Volume
13
Number
1
Pages
41-53
Language
english
Notes
Publication types: Journal Article
Publication Status: ppublish
Abstract
Mutations in the Huntingtin (HTT) gene cause Huntington's disease (HD), a neurodegenerative disorder. As a scaffold protein, HTT is involved in numerous cellular functions, but its normal and pathogenic functions during human forebrain development are poorly understood.
To investigate the developmental component of HD, with a specific emphasis on understanding the functions of wild-type and mutant HTT alleles during forebrain neuron development in individuals carrying HD mutations.
We used CRISPR/Cas9 gene-editing technology to disrupt the ATG region of the HTT gene via non-homologous end joining to produce mono- or biallelic HTT knock-out human induced pluripotent stem cell (iPSC) clones.
We showed that the loss of wild-type, mutant, or both HTT isoforms does not affect the pluripotency of iPSCs or their transition into neural cells. However, we observed that HTT loss causes division impairments in forebrain neuro-epithelial cells and alters maturation of striatal projection neurons (SPNs) particularly in the acquisition of DARPP32 expression, a key functional marker of SPNs. Finally, young post-mitotic neurons derived from HTT-/- human iPSCs display cellular dysfunctions observed in adult HD neurons.
We described a novel collection of isogenic clones with mono- and biallelic HTT inactivation that complement existing HD-hiPSC isogenic series to explore HTT functions and test therapeutic strategies in particular HTT-lowering drugs. Characterizing neural and neuronal derivatives from human iPSCs of this collection, we show evidence that HTT loss or mutation has impacts on neuro-epithelial and striatal neurons maturation, and on basal DNA damage and BDNF axonal transport in post-mitotic neurons.
Keywords
Adult, Humans, Induced Pluripotent Stem Cells/metabolism, Huntington Disease/metabolism, Neurons/metabolism, Corpus Striatum/metabolism, Alleles, Huntingtin Protein/genetics, Huntingtin Protein/metabolism, BDNF, DNA repair, Huntingtin, Huntington’s disease, Induced pluripotent stem cells, iPS, neurodegenerative disease
Pubmed
Web of science
Open Access
Yes
Create date
08/03/2024 16:02
Last modification date
18/05/2024 5:59
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