Neuronal and astrocytic contributions to Huntington's disease dissected with zinc finger protein transcriptional repressors.
Neuronal and astrocytic contributions to Huntington's disease dissected with zinc finger protein transcriptional repressors.
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DOI：
10.1016/j.celrep.2022.111953
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发表时间：
2023-01-31
期刊：
影响因子：
8.8
通讯作者：
中科院分区：
文献类型：
--
作者：
亨廷顿病(HD)是由于亨廷顿蛋白基因(HTT)中CAG重复序列的扩大导致突变的HTT蛋白(MHTT)表达的多聚谷氨酰胺束，包括纹状体神经元和星形胶质细胞。目前尚不清楚是否可以通过降低整个大脑中任何一种细胞的mHTT来减弱体内的病理生理学，神经元和星形胶质细胞在HD中的相对贡献仍不确定。我们使用锌指蛋白(ZFP)转录抑制物在体内细胞选择性地降低mHTT。星形胶质细胞表现出基本功能的丧失，如胆固醇代谢，部分原因是更大的神经元功能障碍，包括神经调节、突触和细胞内信号通路。利用转录学、蛋白质组学、电生理学和行为学，我们剖析了神经元和星形胶质细胞对HD病理生理学的贡献。值得注意的是，全脑递送神经元ZFP可以显著降低mHTT，挽救HD相关的行为和分子表型，并显著延长寿命，这些发现支持翻译发育。
Huntington’s disease (HD) is caused by expanded CAG repeats in the Huntingtin gene (HTT) resulting in expression of mutant HTT proteins (mHTT) with extended polyglutamine tracts, including in striatal neurons and astrocytes. It is unknown if pathophysiology in vivo can be attenuated by lowering mHTT in either cell type throughout the brain, and the relative contributions of neurons and astrocytes to HD remain undefined. We use zinc finger protein (ZFP) transcriptional repressors to cell-selectively lower mHTT in vivo. Astrocytes display loss of essential functions such as cholesterol metabolism that are partly driven by greater neuronal dysfunctions, which encompass neuromodulation, synaptic, and intracellular signaling pathways. Using transcriptomics, proteomics, electrophysiology, and behavior we dissect neuronal and astrocytic contributions to HD pathophysiology. Remarkably, brain wide delivery of neuronal ZFPs results in strong mHTT lowering, rescue of HD-associated behavioral and molecular phenotypes, and significant extension of lifespan, findings that support translational development.
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影响因子：
4.7
作者：
Hoffner, G;Island, ML;Djian, P
通讯作者：
Djian, P
影响因子：
3.7
作者：
Heikkinen T;Bragge T;Bhattarai N;Parkkari T;Puoliväli J;Kontkanen O;Sweeney P;Park LC;Munoz-Sanjuan I
通讯作者：
Munoz-Sanjuan I
影响因子：
25
作者：
Langfelder P;Cantle JP;Chatzopoulou D;Wang N;Gao F;Al-Ramahi I;Lu XH;Ramos EM;El-Zein K;Zhao Y;Deverasetty S;Tebbe A;Schaab C;Lavery DJ;Howland D;Kwak S;Botas J;Aaronson JS;Rosinski J;Coppola G;Horvath S;Yang XW
通讯作者：
Yang XW
影响因子：
25
作者：
Chan KY;Jang MJ;Yoo BB;Greenbaum A;Ravi N;Wu WL;Sánchez-Guardado L;Lois C;Mazmanian SK;Deverman BE;Gradinaru V
通讯作者：
Gradinaru V
影响因子：
3.1
作者：
Ghavami, Afshin;Olsen, Michael;Park, Larry C.
通讯作者：
Park, Larry C.