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How reactive astrocytes contribute to Huntington\u2019s disease is still an open question, especially because their reactive state is poorly reproduced in experimental mouse models.<\/jats:p>\n                  <jats:p>Here, we show that the JAK2-STAT3 pathway, a central cascade controlling astrocyte reactive response, is activated in the putamen of Huntington\u2019s 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\u2019s 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.<\/jats:p>\n                  <jats:p>Together, our results show that the JAK2-STAT3 pathway controls a beneficial proteostasis response in reactive astrocytes in Huntington\u2019s disease, which involves bi-directional signalling with neurons to reduce mutant Huntingtin aggregation, eventually improving disease outcomes.<\/jats:p>","DOI":"10.1093\/brain\/awac068","type":"journal-article","created":{"date-parts":[[2022,2,17]],"date-time":"2022-02-17T15:11:28Z","timestamp":1645110688000},"page":"149-166","source":"Crossref","is-referenced-by-count":74,"title":["Reactive astrocytes promote proteostasis in Huntington\u2019s disease through the JAK2-STAT3 pathway"],"prefix":"10.1093","volume":"146","author":[{"given":"Laurene","family":"Abjean","sequence":"first","affiliation":[{"name":"Universit\u00e9 Paris-Saclay, Commissariat \u00e0 l\u2019Energie Atomique et aux Energies Alternatives, Centre National de la Recherche Scientifique, MIRCen, Laboratoire des Maladies Neurod\u00e9g\u00e9n\u00e9ratives , 92265 Fontenay-aux-Roses , France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucile","family":"Ben Haim","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris-Saclay, Commissariat \u00e0 l\u2019Energie Atomique et aux Energies Alternatives, Centre National de la Recherche Scientifique, MIRCen, Laboratoire des Maladies Neurod\u00e9g\u00e9n\u00e9ratives , 92265 Fontenay-aux-Roses , France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9204-3088","authenticated-orcid":false,"given":"Miriam","family":"Riquelme-Perez","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris-Saclay, Commissariat \u00e0 l\u2019Energie Atomique et aux Energies Alternatives, Centre National de la Recherche Scientifique, MIRCen, Laboratoire des Maladies Neurod\u00e9g\u00e9n\u00e9ratives , 92265 Fontenay-aux-Roses , France"},{"name":"Universit\u00e9 Paris-Saclay, Commissariat \u00e0 l\u2019Energie Atomique et aux Energies Alternatives, Centre National de Recherche en G\u00e9nomique Humaine , 91057 Evry , France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pauline","family":"Gipchtein","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris-Saclay, Commissariat \u00e0 l\u2019Energie Atomique et aux Energies Alternatives, Centre National de la Recherche Scientifique, MIRCen, Laboratoire des Maladies Neurod\u00e9g\u00e9n\u00e9ratives , 92265 Fontenay-aux-Roses , France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C\u00e9line","family":"Derbois","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris-Saclay, Commissariat \u00e0 l\u2019Energie Atomique et aux Energies Alternatives, Centre National de Recherche en G\u00e9nomique Humaine , 91057 Evry , France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie-Ange","family":"Palomares","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris-Saclay, Commissariat \u00e0 l\u2019Energie Atomique et aux Energies Alternatives, Centre National de Recherche en G\u00e9nomique Humaine , 91057 Evry , France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fanny","family":"Petit","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris-Saclay, Commissariat \u00e0 l\u2019Energie Atomique et aux Energies Alternatives, Centre National de la Recherche Scientifique, MIRCen, Laboratoire des Maladies Neurod\u00e9g\u00e9n\u00e9ratives , 92265 Fontenay-aux-Roses , France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne-Sophie","family":"H\u00e9rard","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris-Saclay, Commissariat \u00e0 l\u2019Energie Atomique et aux Energies Alternatives, Centre National de la 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Fontenay-aux-Roses , France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"No\u00e9mie","family":"Robil","sequence":"additional","affiliation":[{"name":"GenoSplice technology , 75013 Paris , France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7440-6394","authenticated-orcid":false,"given":"Mehdi","family":"Kabani","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris-Saclay, Commissariat \u00e0 l\u2019Energie Atomique et aux Energies Alternatives, Centre National de la Recherche Scientifique, MIRCen, Laboratoire des Maladies Neurod\u00e9g\u00e9n\u00e9ratives , 92265 Fontenay-aux-Roses , France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ronald","family":"Melki","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris-Saclay, Commissariat \u00e0 l\u2019Energie Atomique et aux Energies Alternatives, Centre National de la Recherche Scientifique, MIRCen, Laboratoire des Maladies Neurod\u00e9g\u00e9n\u00e9ratives , 92265 Fontenay-aux-Roses , France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pierre","family":"De la Grange","sequence":"additional","affiliation":[{"name":"GenoSplice technology , 75013 Paris , France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexis P","family":"Bemelmans","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris-Saclay, Commissariat \u00e0 l\u2019Energie Atomique et aux Energies Alternatives, Centre National de la Recherche Scientifique, MIRCen, Laboratoire des Maladies Neurod\u00e9g\u00e9n\u00e9ratives , 92265 Fontenay-aux-Roses , France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gilles","family":"Bonvento","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris-Saclay, Commissariat \u00e0 l\u2019Energie Atomique et aux Energies Alternatives, Centre National de la Recherche Scientifique, MIRCen, Laboratoire des Maladies Neurod\u00e9g\u00e9n\u00e9ratives , 92265 Fontenay-aux-Roses , France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Fran\u00e7ois","family":"Deleuze","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris-Saclay, Commissariat \u00e0 l\u2019Energie Atomique et aux Energies Alternatives, Centre National de Recherche en G\u00e9nomique Humaine , 91057 Evry , France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philippe","family":"Hantraye","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris-Saclay, Commissariat \u00e0 l\u2019Energie Atomique et aux Energies Alternatives, Centre National de la Recherche Scientifique, MIRCen, Laboratoire des Maladies Neurod\u00e9g\u00e9n\u00e9ratives , 92265 Fontenay-aux-Roses , 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l\u2019Energie Atomique et aux Energies Alternatives, Centre National de Recherche en G\u00e9nomique Humaine , 91057 Evry , France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Olaso","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris-Saclay, Commissariat \u00e0 l\u2019Energie Atomique et aux Energies Alternatives, Centre National de Recherche en G\u00e9nomique Humaine , 91057 Evry , France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6322-7403","authenticated-orcid":false,"given":"Emmanuel","family":"Brouillet","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris-Saclay, Commissariat \u00e0 l\u2019Energie Atomique et aux Energies Alternatives, Centre National de la Recherche Scientifique, MIRCen, Laboratoire des Maladies Neurod\u00e9g\u00e9n\u00e9ratives , 92265 Fontenay-aux-Roses , France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3312-5956","authenticated-orcid":false,"given":"Maria-Angeles","family":"Carrillo-de Sauvage","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris-Saclay, Commissariat \u00e0 l\u2019Energie Atomique et aux Energies Alternatives, Centre National de la Recherche Scientifique, MIRCen, Laboratoire des Maladies Neurod\u00e9g\u00e9n\u00e9ratives , 92265 Fontenay-aux-Roses , France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3613-4118","authenticated-orcid":false,"given":"Carole","family":"Escartin","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris-Saclay, Commissariat \u00e0 l\u2019Energie Atomique et aux Energies Alternatives, Centre National de la Recherche Scientifique, MIRCen, Laboratoire des Maladies Neurod\u00e9g\u00e9n\u00e9ratives , 92265 Fontenay-aux-Roses , 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