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Huntington disease alters human neurodevelopment

on the August 5, 2020
Huntington disease - like amyotrophic lateral sclerosis and Alzheimer's and Parkinson's disease – is part of the family of diseases that shared a delayed onset in mid-adulthood despite the expression, at least in hereditary cases, of the disease-driving protein from the first days of life. For example, huntingtin, the protein mutated in Huntington disease, is expressed very early in development during which it plays a key role. In mice, mutant huntingtin interferes with several stages of development in certain brain regions, including the cortex. Furthermore, expression of mutant huntingtin restricted to development is sufficient to produce features of Huntington's disease in adult mice suggesting that there is a developmental component to the disease.

Nevertheless, whether early human brain development is altered remained a central question in the field. To answer it, teams led Sandrine Humbert, research director, INSERM (the French National Institute for Health and Medical Research) and group leader at the Grenoble Institut des Neurosciences, and by Alexandra Durr, professor at Sorbonne University and team leader in the Paris Brain Institute at Pitie-Salpêtrière Hospital, Paris had access to fetal tissue from families that terminated their pregnancy in the context of a prenatal test. The developing fetus carried the Huntington disease gene mutation. These tissues showed abnormalities in the developing cortex, including abnormal localization of mutant huntingtin and junction complex proteins, defects in polarity and differentiation of neural precursors, abnormal ciliogenesis, and changes in mitosis and cell cycle progression. These abnormalities disrupt the "division-differentiation" balance of progenitor cells. Progenitor cells come from a pool of dividing cells, some of which differentiate into neurons while the other continues to divide to provide new progenitor cells. In Huntington disease gene carrier embryos, these progenitor cells differentiate more rapidly at the expense of the pool of dividing cells.

This work provides the first direct evidence from human fetuses that brain development is impaired in a neurodegenerative disease with delayed onset. This discovery opens up a field of new investigations aimed at understanding how these early defects contribute to adult pathology and how their compensation is regulated. This discovery also has important implications for the way and stage at which disease-modifying treatments should be considered.


Huntington disease alters human neurodevelopment. M Barnat, M Capizzi, E Aparicio, S Boluda, D Wennagel, R Kacher, R Kassem, S Lenoir, F Agasse, BY Braz, JP Liu, J Ighil, A Tessier, SO Zeitlin, C Duyckaerts, M Dommergues, A Durr, S Humbert. Science, 2020, 10.1126/science.aax3338

Updated on August 11, 2020

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