Research Article

Huntington’s disease alters human neurodevelopment

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Science  14 Aug 2020:
Vol. 369, Issue 6505, pp. 787-793
DOI: 10.1126/science.aax3338

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Neural progenitors disrupted

Symptoms of Huntington's disease (HD) manifest in adulthood despite the aberrant protein being present much earlier in persons carrying the disease-causing mutation. Barnat et al. studied the cellular effects of the HD mutation on human and mouse fetal brain development (see the Perspective by DiFiglia). The authors found that neural progenitor cells at the brain's ventricular zone reach out to both the apical and basal surfaces of the neuroepithelial wall, and their cellular nuclei shuttle back and forth as the cell cycle progresses. With the aberrant protein, these epithelial junctions are disrupted, epithelial polarity is disturbed, and the cell cycle favors premature neuronal differentiation.

Science, this issue p. 787; see also p. 771


Although Huntington’s disease is a late-manifesting neurodegenerative disorder, both mouse studies and neuroimaging studies of presymptomatic mutation carriers suggest that Huntington’s disease might affect neurodevelopment. To determine whether this is actually the case, we examined tissue from human fetuses (13 weeks gestation) that carried the Huntington’s disease mutation. These tissues showed clear abnormalities in the developing cortex, including mislocalization of mutant huntingtin and junctional complex proteins, defects in neuroprogenitor cell polarity and differentiation, abnormal ciliogenesis, and changes in mitosis and cell cycle progression. We observed the same phenomena in Huntington’s disease mouse embryos, where we linked these abnormalities to defects in interkinetic nuclear migration of progenitor cells. Huntington’s disease thus has a neurodevelopmental component and is not solely a degenerative disease.

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