Huntington's disease is caused by polyglutamine (polyQ)-expansion mutations in the CAG tandem repeat of the Huntingtin gene. The central feature of Huntington's disease pathology is the aggregation of mutant Huntingtin (Htt) protein into micrometer-sized inclusion bodies. Soluble mutant Htt states are most proteotoxic and trigger an enhanced risk of death whereas inclusions confer different changes to cellular health, and may even provide adaptive responses to stress. Yet the molecular mechanisms underpinning these changes remain unclear. Using the flow cytometry method of pulse-shape analysis (PulSA) to sort neuroblastoma (Neuro2a) cells enriched with mutant or wild-type Htt into different aggregation states, we clarified which transcriptional signatures were specifically attributable to cells before versus after inclusion assembly. Dampened CREB signalling was the most striking change overall and invoked specifically by soluble mutant Httex1 states. Toxicity could be rescued by stimulation of CREB signalling. Other biological processes mapped to different changes before and after aggregation included NF-kB signalling, autophagy, SUMOylation, transcription regulation by histone deacetylases and BRD4, NAD+ biosynthesis, ribosome biogenesis and altered HIF-1 signalling. These findings open the path for therapeutic strategies targeting key molecular changes invoked prior to, and subsequently to, Httex1 aggregation.

中文翻译：

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突变的Huntingtin外显子1蛋白的不同聚集状态的转录谱揭示了新的亨廷顿舞蹈病途径。

亨廷顿氏病是由亨廷顿基因的CAG串联重复序列中的聚谷氨酰胺（polyQ）扩展突变引起的。亨廷顿舞蹈病病理学的主要特征是突变的亨廷顿（Htt）蛋白聚集成微米大小的包涵体。可溶性突变体Htt状态具有最大的蛋白毒性，并会增加死亡风险，而内含物会给细胞健康带来不同的变化，甚至可能提供对压力的适应性反应。然而，支持这些变化的分子机制仍不清楚。使用脉冲形状分析（PulSA）的流式细胞仪方法将富含突变型或野生型Htt的神经母细胞瘤（Neuro2a）细胞分类为不同的聚集状态，我们弄清了哪些转录特征特别是归因于包涵体组装前后。总体上，最显着的变化是CREB信号的衰减，并且被可溶性突变体Httex1状态特别激活。刺激CREB信号可以拯救毒性。映射到聚集前后不同变化的其他生物学过程包括NF-kB信号传导，自噬，SUMO酰化，组蛋白脱乙酰基酶和BRD4的转录调控，NAD +生物合成，核糖体生物发生和HIF-1信号传导改变。这些发现为针对Httex1聚集之前和之后引发的关键分子变化的治疗策略打开了道路。映射到聚集前后不同变化的其他生物学过程包括NF-kB信号传导，自噬，SUMO酰化，组蛋白脱乙酰基酶和BRD4的转录调控，NAD +生物合成，核糖体生物发生和改变的HIF-1信号传导。这些发现为针对Httex1聚集之前和之后引发的关键分子变化的治疗策略打开了道路。映射到聚集前后不同变化的其他生物学过程包括NF-kB信号传导，自噬，SUMO酰化，组蛋白脱乙酰基酶和BRD4的转录调控，NAD +生物合成，核糖体生物发生和HIF-1信号传导改变。这些发现为针对Httex1聚集之前和之后引发的关键分子变化的治疗策略打开了道路。