Cerebroprotective Role of <i>N</i>⁶-Methyladenosine Demethylase FTO (Fat Mass and Obesity-Associated Protein) After Experimental Stroke.

Abstract

FTO (fat mass and obesity-associated protein) demethylates <i>N</i>⁶-methyladenosine (m⁶A), which is a critical epitranscriptomic regulator of neuronal function. We previously reported that ischemic stroke induces m⁶A 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 m⁶A methylation in poststroke brain damage. 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. FTO overexpression significantly decreased the poststroke m⁶A 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. These results demonstrate that FTO-dependent m⁶A demethylation minimizes long-term sequelae of stroke independent of sex.