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Cell Type-Specific Transcriptomics Reveals that Mutant Huntingtin Leads to Mitochondrial RNA Release and Neuronal Innate Immune Activation.
Neuron ( IF 14.7 ) Pub Date : 2020-07-17 , DOI: 10.1016/j.neuron.2020.06.021
Hyeseung Lee 1 , Robert J Fenster 2 , S Sebastian Pineda 3 , Whitney S Gibbs 4 , Shahin Mohammadi 5 , Jose Davila-Velderrain 5 , Francisco J Garcia 6 , Martine Therrien 1 , Hailey S Novis 4 , Fan Gao 7 , Hilary Wilkinson 8 , Thomas Vogt 8 , Manolis Kellis 3 , Matthew J LaVoie 4 , Myriam Heiman 9
Affiliation  

The mechanisms by which mutant huntingtin (mHTT) leads to neuronal cell death in Huntington’s disease (HD) are not fully understood. To gain new molecular insights, we used single nuclear RNA sequencing (snRNA-seq) and translating ribosome affinity purification (TRAP) to conduct transcriptomic analyses of caudate/putamen (striatal) cell type-specific gene expression changes in human HD and mouse models of HD. In striatal spiny projection neurons, the most vulnerable cell type in HD, we observe a release of mitochondrial RNA (mtRNA) (a potent mitochondrial-derived innate immunogen) and a concomitant upregulation of innate immune signaling in spiny projection neurons. Further, we observe that the released mtRNAs can directly bind to the innate immune sensor protein kinase R (PKR). We highlight the importance of studying cell type-specific gene expression dysregulation in HD pathogenesis and reveal that the activation of innate immune signaling in the most vulnerable HD neurons provides a novel framework to understand the basis of mHTT toxicity and raises new therapeutic opportunities.



中文翻译:

细胞类型特异性转录组学揭示突变亨廷顿蛋白导致线粒体 RNA 释放和神经元先天免疫激活。

突变亨廷顿蛋白 ( mHTT)的机制) 导致亨廷顿氏病 (HD) 中的神经元细胞死亡尚未完全了解。为了获得新的分子见解,我们使用单核 RNA 测序 (snRNA-seq) 和翻译核糖体亲和纯化 (TRAP) 对人类 HD 和小鼠模型中尾状核/壳核(纹状体)细胞类型特异性基因表达变化进行转录组学分析。高清。在纹状体棘突投射神经元(HD 中最脆弱的细胞类型)中,我们观察到线粒体 RNA (mtRNA)(一种有效的线粒体衍生的先天免疫原)的释放以及多刺投射神经元中的先天免疫信号随之上调。此外,我们观察到释放的 mtRNA 可以直接与先天免疫传感器蛋白激酶 R (PKR) 结合。mHTT毒性并带来新的治疗机会。

更新日期:2020-09-10
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