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Background: FTO (fat mass and obesity-associated protein) demethylates N 6 -methyladenosine (m 6 A), which is a critical epitranscriptomic regulator of neuronal function. We previously reported that ischemic stroke induces m 6 A hypermethylation with a simultaneous decrease in FTO expression in neurons. Currently, we evaluated the functional significance of restoring FTO with an adeno-associated virus 9, and thus reducing m 6 A methylation in poststroke brain damage. Methods: Adult male and female C57BL/6J mice were injected with FTO adeno-associated virus 9 (intracerebral) at 21 days prior to inducing transient middle cerebral artery occlusion. Poststroke brain damage (infarction, atrophy, and white matter integrity) and neurobehavioral deficits (motor function, cognition, depression, and anxiety-like behaviors) were evaluated between days 1 and 28 of reperfusion. Results: FTO overexpression significantly decreased the poststroke m 6 A hypermethylation. More importantly, exogenous FTO substantially decreased poststroke gray and white matter damage and improved motor function recovery, cognition, and depression-like behavior in both sexes. Conclusions: These results demonstrate that FTO-dependent m 6 A demethylation minimizes long-term sequelae of stroke independent of sex.

FTO (fat mass and obesity-associated protein) demethylatesAdult male and female C57BL/6J mice were injected with FTO adeno-associated virus 9 (intracerebral) at 21 days prior to inducing transient middle cerebral artery occlusion. Poststroke brain damage (infarction, atrophy, and white matter integrity) and neurobehavioral deficits (motor function, cognition, depression, and anxiety-like behaviors) were evaluated between days 1 and 28 of reperfusion.FTO overexpression significantly decreased the poststroke mThese results demonstrate that FTO-dependent m