Revisiting the outcome of adult wild-type Htt inactivation in the context of HTT-lowering strategies for Huntington's disease.

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Ressource 1Télécharger: Regio et al. 2023.pdf (1491.10 [Ko])
Etat: Public
Version: Final published version
Licence: CC BY 4.0
Document(s) secondaire(s)
Télécharger: Supplementary Table 2_DEG_list.xlsx (6861.25 [Ko])
Etat: Public
Version: Supplementary document
Licence: Non spécifiée
Télécharger: Supplementary Table 3_DEG_SPN.xlsx (33.40 [Ko])
Etat: Public
Version: Supplementary document
Licence: Non spécifiée
Télécharger: Supplementary_material.docx (4053.17 [Ko])
Etat: Public
Version: Supplementary document
Licence: Non spécifiée
ID Serval
serval:BIB_C884DC8D50B7
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
Revisiting the outcome of adult wild-type Htt inactivation in the context of HTT-lowering strategies for Huntington's disease.
Périodique
Brain communications
Auteur⸱e⸱s
Regio S., Vachey G., Goñi E., Duarte F., Rybarikova M., Sipion M., Rey M., Huarte M., Déglon N.
ISSN
2632-1297 (Electronic)
ISSN-L
2632-1297
Statut éditorial
Publié
Date de publication
2023
Peer-reviewed
Oui
Volume
5
Numéro
6
Pages
fcad344
Langue
anglais
Notes
Publication types: Journal Article
Publication Status: epublish
Résumé
Huntingtin-lowering strategies are central to therapeutic approaches for Huntington's disease. Recent studies reported the induction of age- and cell type-specific phenotypes by conditional huntingtin knockout, but these experimental conditions did not precisely mimic huntingtin-lowering or gene-editing conditions in terms of the cells targeted and brain distribution, and no transcriptional profiles were provided. Here, we used the adeno-associated delivery system commonly used in CNS gene therapy programmes and the self-inactivating KamiCas9 gene-editing system to investigate the long-term consequences of wild-type mouse huntingtin inactivation in adult neurons and, thus, the feasibility and safety of huntingtin inactivation in these cells. Behavioural and neuropathological analyses and single-nuclei RNA sequencing indicated that huntingtin editing in 77% of striatal neurons and 16% of cortical projecting neurons in adult mice induced no behavioural deficits or cellular toxicity. Single-nuclei RNA sequencing in 11.5-month-old animals showed that huntingtin inactivation did not alter striatal-cell profiles or proportions. Few differentially expressed genes were identified and Augur analysis confirmed an extremely limited response to huntingtin inactivation in all cell types. Our results therefore indicate that wild-type huntingtin inactivation in adult striatal and projection neurons is well tolerated in the long term.
Mots-clé
Neurology, Cellular and Molecular Neuroscience, Biological Psychiatry, Psychiatry and Mental health, HTT inactivation, Huntington’s disease, gene editing, neural stem cells, viral vectors
Pubmed
Web of science
Open Access
Oui
Financement(s)
Fonds national suisse / 310030_184761
Création de la notice
07/12/2023 23:18
Dernière modification de la notice
20/01/2024 8:11
Données d'usage