Huntington disease (HD) is caused by an expansion mutation of the N-terminal polyglutamine of huntingtin (mHTT). mHTT is ubiquitously present, but it induces noticeable damage to the brain’s striatum, thereby affecting motor, psychiatric, and cognitive functions. The striatal damage and progression of HD are associated with the inflammatory response; however, the underlying molecular mechanisms remain unclear. Here, we report that cGMP-AMP synthase (cGAS), a DNA sensor, is a critical regulator of inflammatory and autophagy responses in HD. Ribosome profiling revealed that the cGAS mRNA has high ribosome occupancy at exon 1 and codon-specific pauses at positions 171 (CCG) and 172 (CGT) in HD striatal cells. Moreover, the protein levels and activity of cGAS (based on the phosphorylated STING and phosphorylated TBK1 levels), and the expression and ribosome occupancy of cGAS-dependent inflammatory genes (Ccl5 and Cxcl10) are increased in HD striatum. Depletion of cGAS diminishes cGAS activity and decreases the expression of inflammatory genes while suppressing the up-regulation of autophagy in HD cells. In contrast, reinstating cGAS in cGAS-depleted HD cells activates cGAS activity and promotes inflammatory and autophagy responses. Ribosome profiling also revealed that LC3A and LC3B, the two major autophagy initiators, show altered ribosome occupancy in HD cells. We also detected the presence of numerous micronuclei, which are known to induce cGAS, in the cytoplasm of neurons derived from human HD embryonic stem cells. Collectively, our results indicate that cGAS is up-regulated in HD and mediates inflammatory and autophagy responses. Thus, targeting the cGAS pathway may offer therapeutic benefits in HD.

亨廷顿病（HD）是由亨廷顿蛋白（mHTT）的N末端多聚谷氨酰胺的扩增突变引起的。mHTT无处不在，但会引起大脑纹状体的明显损伤，从而影响运动，精神病学和认知功能。纹状体的损害和HD的发展与炎症反应有关。然而，潜在的分子机制仍不清楚。在这里，我们报告cGMP-AMP合酶（cGAS），一种DNA传感器，是高清中炎症和自噬反应的关键调节剂。核糖体分析显示cGASmRNA在外显子1的核糖体占有率很高，并且在HD纹状体细胞中位于171（CCG）和172（CGT）位置的密码子特异性停顿。此外，HD纹状体中cGAS的蛋白水平和活性（基于磷酸化的STING和磷酸化的TBK1水平）以及cGAS依赖性炎症基因（Ccl5和Cxcl10）的表达和核糖体占有率均增加。cGAS的消耗减少了cGAS的活性并降低了炎症基因的表达，同时抑制了HD细胞自噬的上调。相反，在耗尽cGAS的HD细胞中恢复cGAS可激活cGAS活性并促进炎症和自噬反应。核糖体分析还显示LC3A和LC3B，两个主要的自噬引发剂，显示出HD细胞中核糖体的占有率发生了变化。我们还检测到在衍生自人类HD胚胎干细胞的神经元细胞质中存在大量诱导cGAS的微核。总的来说，我们的结果表明cGAS在HD中上调，并介导炎症和自噬反应。因此，靶向cGAS途径可以在HD中提供治疗益处。