Cerebroprotective Role of N6-Methyladenosine Demethylase FTO (Fat Mass and Obesity-Associated Protein) After Experimental Stroke

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.

Automated summary

Ischemic stroke leads to increased m(6)A levels and decreased FTO expression in neurons. This study demonstrates that restoring FTO and reducing m(6)A methylation can alleviate poststroke brain damage and improve motor function, cognition, and depression-like behavior.