Cyclic GMP-AMP synthase promotes the inflammatory and autophagy responses in Huntington disease

Huntington disease (HD) is caused by an expansion mutation of the N -terminal polyglutamine of huntingtin (mHTT). mHTT is ubiq- uitously present, but it induces noticeable damage to the brain 's striatum, thereby affecting motor, psychiatric, and cognitive func- tions. The striatal damage and progression of HD are associated with the inflammatory response; however, the underlying molec- ular mechanisms remain unclear. Here, we report that cGMP-AMP synthase (cGAS), a DNA sensor, is a critical regulator of inflamma- tory 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 de- creases 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 pro- motes inflammatory and autophagy responses. Ribosome profil- ing 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 auto- phagy responses. Thus, targeting the cGAS pathway may offer therapeutic benefits in HD.