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

Scientists studied a protein called PKCβ in mice that show autism-like behaviors. They found this protein was lower in the brains of these mice. When they increased PKCβ levels, it triggered a chain reaction of other proteins that helped protect brain cells from dying. This led to improvements in social behavior and exploration in the mice, suggesting PKCβ might be important for brain health in autism.

This preclinical study investigated protein kinase C beta (PKCβ) in autism using EN2 knockout mice as an autism model. Researchers found PKCβ was downregulated in brain tissues of these mice. The study demonstrated that PKCβ works through a molecular pathway involving FTO, PGC-1α, and UCP1 proteins to regulate neuron function. When PKCβ was overexpressed, it activated this pathway, leading to reduced neuron death and improved autism-like behaviors including enhanced sociability and spatial exploration.

The mechanism involves PKCβ stabilizing FTO protein, which then affects RNA modification of PGC-1α, ultimately influencing UCP1 expression and protecting neurons from apoptosis.

This preclinical research identifies PKCβ and its downstream pathway as potential therapeutic targets for autism. However, translation to humans requires extensive validation. The neuroprotective mechanisms discovered may inform future drug development strategies targeting neuron survival and social behavior improvements in autism.

Single animal model study with unclear sample size. Findings limited to EN2 knockout mice may not generalize to human autism or other autism models. No control group details provided. Molecular mechanisms require validation in human studies.

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 (PKCβ) in the regulation of neuron activity in an autism model. The expression of PKCβ 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 PKCβ on fat mass and obesity-associated protein (FTO) as well as between PGC-1α and uncoupling protein 1 (UCP1) were characterized. The effect of FTO on the N-methyladenosine (m6A) modification level of proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) was assayed. Following transfection of overexpressed PKCβ and/or silenced UCP1, effects of PKCβ and UCP1 in autism-like behaviors in EN2mice were analyzed. Results showed that PKCβ was downregulated in EN2mouse brain tissues or neurons.

PKCβ promoted the expression and stability of FTO, which downregulated the m6A modification level of PGC-1α to promote its expression. Moreover, PGC-1α positively targeted the expression of UCP1. PKCβ knockdown enhanced sociability and spatial exploration ability, and reduced neuron apoptosis in EN2mouse models of autism, which was reversed by UCP1 overexpression. Collectively, PKCβ overexpression leads to activation of the FTO/m6A/PGC-1α/UCP1 axis, thus inhibiting neuron apoptosis and providing neuroprotection in mice with autism-like behavior.