Stress-induced helicase DHX36 controls neuroinflammation

Neurons in the aging brain experience sustained inflammatory, proteostatic, and genotoxic stress, accompanied by the accumulation of non-canonical nucleic acid structures such as G-quadruplexes (G4s). Using a G4-binding probe and mass spectrometry, we identified the G4 helicase DHX36 enriched in the aged mouse brain, prompting further investigation into its regulation during aging. DHX36 expression was elevated in neurons from aged mouse and human brains and further increased in a tauopathy mouse model and Alzheimer's disease brain. Unexpectedly, pharmacological stabilization of G4s with pyridostatin (PDS) reduced Dhx36 mRNA and protein levels in cultured mouse cortical neurons, indicating that G4 stabilization alone is insufficient to induce DHX36. In contrast, aging-relevant stressors, including inflammatory, ER, and genotoxic stress, robustly increased DHX36 expression and nuclear G4-positive puncta in cultured neurons. Transcriptomic profiling in neurons revealed that DHX36 suppresses neuroinflammatory pathways and modulates genes associated with inflammation, senescence, and chromatin regulation. DHX36 reduced expression of the chromatin architectural factors Hmga1 and Hmga2, identifying them as downstream targets. An ATPase-deficient DHX36 mutant (E335A) reproduced the major transcriptional effects of wild-type DHX36, indicating that they do not require ATP-dependent unwinding. These findings identify DHX36 as a stress-responsive G4 helicase that links aging-relevant stress to transcriptional regulation in neurons and suggest a role in maintaining neuronal homeostasis during aging and neurodegeneration.