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

Significance Huntington disease (HD) is a genetic disorder caused by glutamine-expansion in the huntingtin (mHTT) protein, which affects motor, psychiatric, and cognitive function, but the mechanisms remain unclear. mHTT is known to induce DNA damage and affect autophagy, both associated with inflammatory responses, but what mediates all these were unknown. Here we report that cGAS, a DNA damage sensor, is highly upregulated in the striatum of a mouse model and HD human patient’s tissue. We found ribosomes, which make proteins, are robustly accumulated on the cGAS mRNA in HD cells. cGAS depletion decreases—and cGAS expression increases—both inflammatory and autophagy responses in HD striatal cells. Thus, cGAS is a therapeutic target for HD. Blocking cGAS will prevent/slow down HD symptoms.