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.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
Abbreviations: AAV = Adeno-Associated Virus; DARPP32 = Dopamine- and cAMP-Regulated neuronal Phosphoprotein; BSA = Bovine Serum Albumin; DNAJB1 = DnaJ heat shock protein family (Hsp40) member B1; FACS = Fluorescence-Activated Cell Sorting; GFAP = Glial Fibrillary Acidic Protein; Glutamate Chemical Exchange Saturation transfer = gluCEST; HBSS = Hank’s Balanced Salt Solution; HSP = Heat Shock Proteins; JAK = Janus Kinase; LV = Lentiviral Vector; mHTT = mutant Huntingtin; RT = Room Temperature; SDS = Sodium Dodecyl Sulfate; SOCS3 = Suppressor Of Cytokine Signalling 3; STAT3 = Signal Transducer and Activator of Transcription 3; Tx = Triton X-100; Ub = Ubiquitin; UPS = Ubiquitin-Proteasome System; WT = Wild type.
This version of the manuscript has been revised to integrate new results and analysis (new figure 4, new panels in figure 5, new figure 8C, new supplementary figure 1D and 2E). Three authors have been added.