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Article Dans Une Revue Neuron Année : 2022

Developmental Defects in Huntington's Disease Show That Axonal Growth and Microtubule Reorganization Require NUMA1

Résumé

Although the classic symptoms of Huntington's disease (HD) manifest in adulthood, neural progenitor cell behavior is already abnormal by 13~weeks' gestation. To determine how these developmental defects evolve, we turned to cell and mouse models. We found that layer II/III neurons that normally connect the hemispheres are limited in their growth in HD by microtubule bundling defects within the axonal growth cone, so that fewer~axons cross the corpus callosum. Proteomic analyses of the growth cones revealed that NUMA1 (nuclear/mitotic apparatus protein 1) is downregulated in HD by miR-124. Suppressing NUMA1 in wild-type cells~recapitulates the microtubule and axonal growth defects of HD, whereas raising NUMA1 levels with antagomiR-124 or stabilizing microtubules with epothilone B restores microtubule organization and rescues axonal growth. NUMA1 therefore regulates the microtubule network in the growth cone, and HD, which is traditionally conceived as a disease of intracellular trafficking, also disturbs the cytoskeletal network.
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hal-03605365 , version 1 (08-01-2024)

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Paternité - Pas d'utilisation commerciale

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Mariacristina Capizzi, Rémi Carpentier, Eric Denarier, Annie Adrait, Rayane Kassem, et al.. Developmental Defects in Huntington's Disease Show That Axonal Growth and Microtubule Reorganization Require NUMA1. Neuron, 2022, 110 (1), pp.36-50.e5. ⟨10.1016/j.neuron.2021.10.033⟩. ⟨hal-03605365⟩
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