In vivo and in vitro characterization of the p66ShcA inactivation: axonal and neuronal protection in the context of multiple sclerosis

Multiple sclerosis (MS) involves both inflammation and neurodegeneration, with mitochondrial dysfunction and oxidative stress playing key roles. Using the EAE mouse model, we investigated p66ShcA (p66), a redox enzyme that promotes mitochondrial ROS production. p66-knockout mice exhibited reduced clinical severity and axonal damage despite similar inflammation compared to wild-type mice. Neuronal cultures from p66-KO mice showed greater resistance to oxidative stress and preserved mitochondrial integrity. These findings implicate p66 in pathways leading to mitochondrial permeability transition pore activation and neurodegeneration, suggesting p66 inhibition as a potential therapeutic strategy for MS.