دورية أكاديمية
Mono- and Biallelic Inactivation of Huntingtin Gene in Patient-Specific Induced Pluripotent Stem Cells Reveal HTT Roles in Striatal Development and Neuronal Functions.
| العنوان: | 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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| المؤلفون: | Louessard M; Université Paris-Saclay, CEA, Molecular Imaging Research Center, Fontenay-aux-Roses, France.; Université Paris-Saclay, CEA, CNRS, Laboratoire des Maladies Neurodégénératives: Mécanismes, Thérapies, Imagerie, Fontenay-aux-Roses, France.; Université Paris-Saclay, Inserm, Univ Evry, Institut des Cellules Souches pour le Traitement et l'étude des Maladies Monogéniques, Corbeil-Essonne, France., Cailleret M; Université Paris-Saclay, Inserm, Univ Evry, Institut des Cellules Souches pour le Traitement et l'étude des Maladies Monogéniques, Corbeil-Essonne, France., Jarrige M; CECS/AFM, Institut des Cellules Souches pour le Traitement et l'étude des Maladies Monogéniques, Corbeil-Essonne, France., Bigarreau J; Université Paris-Saclay, Inserm, Univ Evry, Institut des Cellules Souches pour le Traitement et l'étude des Maladies Monogéniques, Corbeil-Essonne, France., Lenoir S; Univ. Grenoble Alpes, Inserm, U1216, CHU Grenoble Alpes, Grenoble Institut Neuroscience, GIN, Grenoble, France., Dufour N; Université Paris-Saclay, CEA, Molecular Imaging Research Center, Fontenay-aux-Roses, France.; Université Paris-Saclay, CEA, CNRS, Laboratoire des Maladies Neurodégénératives: Mécanismes, Thérapies, Imagerie, Fontenay-aux-Roses, France., Rey M; Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), Department of Clinical Neurosciences (DNC), and Neuroscience Research Center (CRN), Laboratory of Cellular and Molecular Neurotherapies, Lausanne, Switzerland., Saudou F; Univ. Grenoble Alpes, Inserm, U1216, CHU Grenoble Alpes, Grenoble Institut Neuroscience, GIN, Grenoble, France., Deglon N; Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), Department of Clinical Neurosciences (DNC), and Neuroscience Research Center (CRN), Laboratory of Cellular and Molecular Neurotherapies, Lausanne, Switzerland., Perrier AL; Université Paris-Saclay, CEA, Molecular Imaging Research Center, Fontenay-aux-Roses, France.; Université Paris-Saclay, CEA, CNRS, Laboratoire des Maladies Neurodégénératives: Mécanismes, Thérapies, Imagerie, Fontenay-aux-Roses, France.; Université Paris-Saclay, Inserm, Univ Evry, Institut des Cellules Souches pour le Traitement et l'étude des Maladies Monogéniques, Corbeil-Essonne, France. |
| المصدر: | Journal of Huntington's disease [J Huntingtons Dis] 2024; Vol. 13 (1), pp. 41-53. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: IOS Press Country of Publication: Netherlands NLM ID: 101589965 Publication Model: Print Cited Medium: Internet ISSN: 1879-6400 (Electronic) Linking ISSN: 18796397 NLM ISO Abbreviation: J Huntingtons Dis Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Amsterdam, The Netherlands : IOS Press |
| مواضيع طبية MeSH: | Induced Pluripotent Stem Cells*/metabolism , Huntington Disease*/metabolism, Adult ; Humans ; Neurons/metabolism ; Corpus Striatum/metabolism ; Alleles ; Huntingtin Protein/genetics ; Huntingtin Protein/metabolism |
| مستخلص: | Background: 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. Objective: 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. Methods: 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. Results: 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. Conclusions: 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. |
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| فهرسة مساهمة: | Keywords: BDNF; DNA repair; Huntingtin; Huntington’s disease; Induced pluripotent stem cells; iPS; neurodegenerative disease |
| المشرفين على المادة: | 0 (Huntingtin Protein) 0 (HTT protein, human) |
| تواريخ الأحداث: | Date Created: 20240301 Date Completed: 20240401 Latest Revision: 20240516 |
| رمز التحديث: | 20240516 |
| مُعرف محوري في PubMed: | PMC11091579 |
| DOI: | 10.3233/JHD-231509 |
| PMID: | 38427495 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1879-6400 |
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| DOI: | 10.3233/JHD-231509 |