Protein kinase C beta relieves autism-like behavior in EN2 knockout mice via upregulation of the FTO/PGC-1 alpha/UCP1 axis

Increasing evidence suggests that disruption of neuron activity contributes to the autistic phenotype. Thus, we aimed in this study to explore the role of protein kinase C beta (PKC beta) in the regulation of neuron activity in an autism model. The expression of PKC beta in the microarray data of autism animal models was obtained from the Gene Expression Omnibus database. Then, mice with autism-like behavior were prepared in EN2 knockout ((-/-)) mice. The interaction between PKC beta on fat mass and obesity-associated protein (FTO) as well as between PGC-1 alpha and uncoupling protein 1 (UCP1) were characterized. The effect of FTO on the N-6-methyladenosine (m6A) modification level of proliferator-activated receptor gamma coactivator 1-alpha (PGC-1 alpha) was assayed. Following transfection of overexpressed PKC beta and/or silenced UCP1, effects of PKC beta and UCP1 in autism-like behaviors in EN2(-/-) mice were analyzed. Results showed that PKC beta was downregulated in EN2(-/-) mouse brain tissues or neurons. PKC beta promoted the expression and stability of FTO, which downregulated the m6A modification level of PGC-1 alpha to promote its expression. Moreover, PGC-1 alpha positively targeted the expression of UCP1. PKC beta knockdown enhanced sociability and spatial exploration ability, and reduced neuron apoptosis in EN2(-/-) mouse models of autism, which was reversed by UCP1 overexpression. Collectively, PKC beta overexpression leads to activation of the FTO/m6A/PGC-1 alpha/UCP1 axis, thus inhibiting neuron apoptosis and providing neuroprotection in mice with autism-like behavior.