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

• Published in: Proceedings of the National Academy of Sciences - PNAS 2020-07, Vol.117 (27), p.15989-15999
• Main Authors: Sharma, Manish, Rajendrarao, Sumitha, Shahani, Neelam, Ramírez-Jarquín, Uri Nimrod, Subramaniam, Srinivasa
• Format: Article
• Language: English
• Subjects: AMP; Animals; Autophagy; Autophagy - physiology; Biological Sciences; Brain damage; Brain injury; Chemokine CCL5 - metabolism; Chemokine CXCL10 - metabolism; Cognitive ability; Corpus Striatum - metabolism; CXCL10 protein; Cyclic GMP; Cytoplasm; Deoxyribonucleic acid; Depletion; DNA; Embryo cells; Embryonic Stem Cells; Gene expression; Genes; Humans; Huntingtin; Huntingtin Protein - metabolism; Huntington Disease - genetics; Huntington Disease - metabolism; Huntington's disease; Huntingtons disease; Inflammation; Inflammatory response; Mice; Mice, Inbred C57BL; Mice, Knockout; Micronuclei; Microtubule-Associated Proteins - metabolism; Molecular modelling; mRNA; Mutation; Neostriatum; Neostriatum - metabolism; Neurons - metabolism; Nucleotidyltransferases - genetics; Nucleotidyltransferases - metabolism; Occupancy; Phagocytosis; Phosphorylation; Polyglutamine; Protein-Serine-Threonine Kinases - metabolism; Stem cells; Transcriptome; Trinucleotide repeat diseases; Up-Regulation
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2002144117

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.