亨廷顿蛋白
神经退行性变
蛋白质稳态
亨廷顿病
生物
细胞生物学
亨廷顿蛋白
聚谷氨酰胺束
星形胶质细胞
神经科学
中枢神经系统
疾病
医学
内科学
作者
Laurene Abjean,Lucile Ben Haim,Miriam Riquelme-Pérez,Pauline Gipchtein,Céline Derbois,Marie-Ange Palomares,Fanny Petit,Anne‐Sophie Hérard,Marie‐Claude Gaillard,Martine Guillermier,Mylène Gaudin-Guérif,Gwennaëlle Aurégan,Nisrine Sagar,Cameron Héry,Noëlle Dufour,Noémie Robil,Mehdi Kabani,Ronald Melki,Pierre de la Grange,Alexis‐Pierre Bemelmans
出处
期刊:Brain
[Oxford University Press]
日期:2022-02-17
卷期号:146 (1): 149-166
被引量:52
标识
DOI:10.1093/brain/awac068
摘要
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.
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