Reactive astrocytes promote proteostasis in Huntington’s disease through the JAK2-STAT3 pathway - Archive ouverte HAL
Article Dans Une Revue Brain - A Journal of Neurology Année : 2023

Reactive astrocytes promote proteostasis in Huntington’s disease through the JAK2-STAT3 pathway

Laurene Abjean
  • Fonction : Auteur
Lucile Ben Haim
  • Fonction : Auteur
Miriam Riquelme-Perez
Pauline Gipchtein
  • Fonction : Auteur
Céline Derbois
  • Fonction : Auteur
Marie-Ange Palomares
  • Fonction : Auteur
Fanny Petit
  • Fonction : Auteur
Anne-Sophie Hérard
Marie-Claude Gaillard
  • Fonction : Auteur
Martine Guillermier
  • Fonction : Auteur
Mylène Gaudin-Guérif
  • Fonction : Auteur
Gwennaëlle Aurégan
  • Fonction : Auteur
Nisrine Sagar
  • Fonction : Auteur
Cameron Héry
  • Fonction : Auteur
Noëlle Dufour
  • Fonction : Auteur
Noémie Robil
  • Fonction : Auteur
Mehdi Kabani
Ronald Melki
  • Fonction : Auteur
Pierre de la Grange
  • Fonction : Auteur
Alexis Bemelmans
  • Fonction : Auteur
Gilles Bonvento
  • Fonction : Auteur
Jean-François Deleuze
  • Fonction : Auteur
Philippe Hantraye
  • Fonction : Auteur
Julien Flament
Eric Bonnet
  • Fonction : Auteur
Solène Brohard
  • Fonction : Auteur
  • PersonId : 1404223
  • IdHAL : brohards
Robert Olaso
  • Fonction : Auteur
Maria-Angeles Carrillo-de Sauvage
Carole Escartin

Résumé

Abstract Huntington’s disease is a fatal neurodegenerative disease characterized by striatal neurodegeneration, aggregation of mutant Huntingtin and the presence of reactive astrocytes. Astrocytes are important partners for neurons and engage in a specific reactive response in Huntington’s disease that involves morphological, molecular and functional changes. How reactive astrocytes contribute to Huntington’s disease is still an open question, especially because their reactive state is poorly reproduced in experimental mouse models. Here, we show that the JAK2-STAT3 pathway, a central cascade controlling astrocyte reactive response, is activated in the putamen of Huntington’s disease patients. Selective activation of this cascade in astrocytes through viral gene transfer reduces the number and size of mutant Huntingtin aggregates in neurons and improves neuronal defects in two complementary mouse models of Huntington’s disease. It also reduces striatal atrophy and increases glutamate levels, two central clinical outcomes measured by non-invasive magnetic resonance imaging. Moreover, astrocyte-specific transcriptomic analysis shows that activation of the JAK2-STAT3 pathway in astrocytes coordinates a transcriptional program that increases their intrinsic proteolytic capacity, through the lysosomal and ubiquitin-proteasome degradation systems. This pathway also enhances their production and exosomal release of the co-chaperone DNAJB1, which contributes to mutant Huntingtin clearance in neurons. Together, our results show that the JAK2-STAT3 pathway controls a beneficial proteostasis response in reactive astrocytes in Huntington’s disease, which involves bi-directional signalling with neurons to reduce mutant Huntingtin aggregation, eventually improving disease outcomes.

Dates et versions

hal-04312671 , version 1 (28-11-2023)

Identifiants

Citer

Laurene Abjean, Lucile Ben Haim, Miriam Riquelme-Perez, Pauline Gipchtein, Céline Derbois, et al.. Reactive astrocytes promote proteostasis in Huntington’s disease through the JAK2-STAT3 pathway. Brain - A Journal of Neurology , 2023, 146 (1), pp.149-166. ⟨10.1093/brain/awac068⟩. ⟨hal-04312671⟩
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