1. Reactive astrocytes promote proteostasis in Huntington’s disease through the JAK2-STAT3 pathway
- Author
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Laurene Abjean, Lucile Ben Haim, Miriam Riquelme-Perez, Pauline Gipchtein, Céline Derbois, Marie-Ange Palomares, Fanny Petit, Anne-Sophie Hérard, Marie-Claude Gaillard, Martine Guillermier, Mylène Gaudin-Guérif, Gwenaelle Aurégan, Nisrine Sagar, Cameron Héry, Noëlle Dufour, Noémie Robil, Mehdi Kabani, Ronald Melki, Pierre De la Grange, Alexis P. Bemelmans, Gilles Bonvento, Jean-François Deleuze, Philippe Hantraye, Julien Flament, Eric Bonnet, Solène Brohard, Robert Olaso, Emmanuel Brouillet, Maria-Angeles Carrillo-de Sauvage, Carole Escartin, Laboratoire des Maladies Neurodégénératives - UMR 9199 (LMN), Service MIRCEN (MIRCEN), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Centre National de Recherche en Génomique Humaine (CNRGH), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), GenoSplice [Paris], Fondation maladies rares (GenOmic_2019-0203, Program High throughput sequencing and rare diseases), Association Huntington France, 'Region Ile-de-France' via the 'DIM Cerveau et Pensée', Fondation pour la Recherche Medicale fellowship (ARF201909009244), ANR-10-INBS-04/ FranceBioImagingANR‐ 11‐ IDEX‐003‐02/ Saclay Plant SciencesFrance Génomique national infrastructure, funded by the « Investissements d’Avenir » program managed by the French National Research Agency (ANR-10-INBS-09), ANR-16-TERC-0016,DecodAstro,Decoder la complexité de la réactivité astrocytaire dans les maladies neurodégénératives(2016), ANR-20-CE16-0012,STERO-HD,Signalisation des stérols dans le striatum et effets protecteurs dans la Maladie de Huntington(2020), ANR-17-CE12-0027,EpiHD,Rôle des mécanismes épigénétiques dans la maladie de Huntington(2017), ANR-17-RAR3-0008,TreatPolyQ,Allele-specific lowering of mutant polyQ proteins as treatment for Huntington disease, spinocerebellar ataxia type 3 and spinocerebellar ataxia type 7(2017), ANR-11-INBS-0011,NeurATRIS,Infrastructure de Recherche Translationnelle pour les Biothérapies en Neurosciences(2011), and ANR-11-EQPX-0029,MORPHOSCOPE 2,Imagerie et reconstruction multiéchelles de la morphogenèse. (Plateforme d'innovation technologique et méthodologique pour l'imagerie in vivo et la reconstruction des dynamiques multiéchelles de la morphogenèse)(2011)
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congenital, hereditary, and neonatal diseases and abnormalities ,Huntingtin ,neuron-astrocyte interactions ,viral vectors ,Mutant ,JAK2-STAT3 signalling ,03 medical and health sciences ,0302 clinical medicine ,Huntington's disease ,mental disorders ,medicine ,neurodegenerative diseases ,DNAJB1 ,030304 developmental biology ,0303 health sciences ,Chemistry ,Putamen ,Neurodegeneration ,medicine.disease ,Microvesicles ,3. Good health ,Cell biology ,Proteostasis ,[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,Neurology (clinical) ,aggregated protein clearance ,030217 neurology & neurosurgery - 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.
- Published
- 2021
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