1. Faulty neuronal determination and cell polarization are reverted by modulating HD early phenotypes.
- Author
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Conforti, P., Besusso, D., Bocchi, V. D., Faedo, A., Cesana, E., Rossetti, G., Ranzani, V., Svendsen, C. N., Thompson, L. M., Toselli, M., Biella, G., Pagani, M., and Cattaneo, E.
- Subjects
HUNTINGTON disease ,NEURODEVELOPMENTAL treatment ,PHENOTYPES ,PLURIPOTENT stem cells ,CYTOARCHITECTONICS ,PATIENTS - Abstract
Increasing evidence suggests that early neurodevelopmental defects in Huntington's disease (HD) patients could contribute to the later adult neurodegenerative phenotype. Here, by using HD-derived induced pluripotent stem cell lines, we report that early telencephalic induction and late neural identity are affected in cortical and striatal populations. We show that a large CAG expansion causes complete failure of the neuro-ectodermal acquisition, while cells carrying shorter CAGs repeats show gross abnormalities in neural rosette formation as well as disrupted cytoarchitecture in cortical organoids. Gene-expression analysis showed that control organoid overlapped with mature human fetal cortical areas, while HD organoids correlated with the immature ventricular zone/subventricular zone. We also report that defects in neuroectoderm and rosette formation could be rescued by molecular and pharmacological approaches leading to a recovery of striatal identity. These results show that mutant huntingtin precludes normal neuronal fate acquisition and highlights a possible connection between mutant huntingtin and abnormal neural development in HD. [ABSTRACT FROM AUTHOR]
- Published
- 2018
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