Highlights d Cul3 mutant mice exhibits social behavioral deficits and anxiety-like behaviors d CUL3 deficiency impairs neurotransmission, excitability, and E-I balance d Protein translation and synaptic vesicle turnover are increased in Cul3 mutant mice d Inhibiting protein translation rescues social behavior and neurotransmission deficits

During aging, acetylcholine receptor (AChR) clusters become fragmented and denervated at the neuromuscular junction (NMJ). Underpinning molecular mechanisms are not well understood. We showed that LRP4, a receptor for agrin and critical for NMJ formation and maintenance, was reduced at protein level in aged mice, which was associated with decreased MuSK tyrosine phosphorylation, suggesting compromised agrin-LRP4-MuSK signaling in aged muscles. Transgenic expression of LRP4 in muscles alleviated AChR fragmentation and denervation and improved neuromuscular transmission in aged mice. LRP4 ubiquitination was augmented in aged muscles, suggesting increased LRP4 degradation as a mechanism for reduced LRP4. We found that sarcoglycan α (SGα) interacted with LRP4 and delayed LRP4 degradation in cotransfected cells. AAV9-mediated expression of SGα in muscles mitigated AChR fragmentation and denervation and improved neuromuscular transmission in aged mice. These observations support a model where compromised agrin-LRP4-MuSK signaling serves as a pathological mechanism of age-related NMJ decline and identify a novel function of SGα in stabilizing LRP4 for NMJ stability in aged mice. This study provides evidence that LRP4, a receptor of agrin that is critical for NMJ formation and maintenance, is reduced at protein level in aged muscles. Transgenic expression of LRP4 in muscles ameliorates AChR fragmentation and denervation and improves neuromuscular transmission in aged mice, demonstrating a critical role of the agrin-LRP4-MuSK signaling. Our study also reveals a novel function of SGα to prevent LRP4 degradation in aged muscles. Finally, we show that NMJ decline in aged mice can be mitigated by AAV9-mediated expression of SGα in muscles. These observations provide insight into pathological mechanisms of age-related NMJ decline and suggest that improved agrin-LRP4-MuSK signaling may be a target for potential therapeutic intervention.

A sustainable and efficient reaction system for enzymatic oil modification is imperative for the food industry. Given the interfacial activation effect of lipase, the sufficient oil–water interface is vital for excellent catalytic activity of lipase. In the present study, a Pickering emulsion reaction system was prepared through directly using reactants as the oil phase and stabilized by mesoporous carbon spheres (MCS) after immobilization of lipase AYS (Candida rugosa, lipase@MCS). Lipase@MCS worked as both the emulsifier and catalyst. Each droplet in the Pickering emulsion was regarded as a microreactor with the reactants in the oil phase, and the removal of the product H2O “pushed” the reaction forward. Taking advantage of the adequate oil–water interface for “lid” opening of lipase and rapid mass transfer in MCS, the Pickering emulsion exhibited excellent enzymatic activity toward phytosterol esterification and transesterification, achieving 95.0% conversion after 1.5 h and catalytic efficiency (CE) of 6.8 mmol g–1 h–1 under nonequilibrium conditions. It is the best performance reported currently with the shortest reaction time, minimal amount of catalyst, and the highest CE (19-fold higher than free lipase one-phase reaction system). Immobilization of lipase on the MCS not only endowed the lipase with exceptional recyclability but also afforded a shield to protect the enzyme from deactivation in a harsh environment, as evidenced by the thermotolerance and recycling test results. This paper paves the way to advancing progress in enzyme-immobilized Pickering emulsion as a sustainable and high-efficiency platform for biocatalysis application.

Adult neurogenesis in the hippocampus may represent a form of plasticity in brain functions including mood, learning and memory. However, mechanisms underlying neural stem/progenitor cells (NSPCs) proliferation are not well understood. We found that Agrin, a factor critical for neuromuscular junction formation, is elevated in the hippocampus of mice that are stimulated by enriched environment (EE). Genetic deletion of the Agrn gene in excitatory neurons decreases NSPCs proliferation and increases depressive-like behavior. Low-density lipoprotein receptor-related protein 4 (Lrp4), a receptor for Agrin, is expressed in hippocampal NSPCs and its mutation blocked basal as well as EE-induced NSPCs proliferation and maturation of newborn neurons. Finally, we show that Lrp4 interacts with and activates receptor tyrosine kinase-like orphan receptor 2 (Ror2); and Ror2 mutation impairs NSPCs proliferation. Together, these observations identify a role of Agrin-Lrp4-Ror2 signaling for adult neurogenesis, uncovering previously unexpected functions of Agrin and Lrp4 in the brain.