The ZIKA virus (ZIKV) evades the host immune response by degrading STAT2 through its NS5 protein, thereby inhibiting type I interferon (IFN)-mediated antiviral immunity. However, the molecular mechanism underlying this process has remained elusive. In this study, we performed a genome-wide CRISPR/Cas9 screen, revealing that ZSWIM8 as the substrate receptor of Cullin3-RING E3 ligase is required for NS5-mediated STAT2 degradation. Genetic depletion of ZSWIM8 and CUL3 substantially impeded NS5-mediated STAT2 degradation. Biochemical analysis illuminated that NS5 enhances the interaction between STAT2 and the ZSWIM8–CUL3 E3 ligase complex, thereby facilitating STAT2 ubiquitination. Moreover, ZSWIM8 knockout endowed A549 and Huh7 cells with partial resistance to ZIKV infection and protected cells from the cytopathic effects induced by ZIKV, which was attributed to the restoration of STAT2 levels and the activation of IFN signaling. Subsequent studies in a physiologically relevant model, utilizing human neural progenitor cells, demonstrated that ZSWIM8 depletion reduced ZIKV infection, resulting from enhanced IFN signaling attributed to the sustained levels of STAT2. Our findings shed light on the role of ZIKV NS5, serving as the scaffold protein, reprograms the ZSWIM8–CUL3 E3 ligase complex to orchestrate STAT2 proteasome-dependent degradation, thereby facilitating evasion of IFN antiviral signaling. Our study provides unique insights into ZIKV–host interactions and holds promise for the development of antivirals and prophylactic vaccines.

MicroRNA-218 (miR-218) has been linked to several cognition related neurodegenerative and neuropsychiatric disorders. However, whether miR-218 plays a direct role in cognitive functions remains unknown. Here, using the miR-218 knockout (KO) mouse model and the sponge/overexpression approaches, we showed that miR-218-2 but not miR-218-1 could bidirectionally regulate the contextual and spatial memory in the mice. Furthermore, miR-218-2 deficiency induced deficits in the morphology and presynaptic neurotransmitter release in the hippocampus to impair the long term potentiation. Combining the RNA sequencing analysis and luciferase reporter assay, we identified complement component 3 (C3) as a main target gene of miR-218 in the hippocampus to regulate the presynaptic functions. Finally, we showed that restoring the C3 activity in the miR-218-2 KO mice could rescue the synaptic and learning deficits. Therefore, miR-218-2 played an important role in the cognitive functions of mice through C3, which can be a mechanism for the defective cognition of miR-218 related neuronal disorders. Significance Several neurodegenerative and neuropsychiatric disorders with cognitive symptoms show an abnormal expression of microRNA-218 (miR-218). In this study, we demonstrated that miR-218 regulated presynaptic functions and learning related behaviors through targeting the 3′-untranslated region (UTR) of the mRNA of complement component 3 (C3), a central component of the immune system. This finding may represent a common mechanism for the defective cognition of multiple neuronal disorders with miR-218 deficits and provide a strategy for the development of new therapy.

Parkinson's disease (PD) is a neurodegenerative disease characterized by the degeneration of dopaminergic (DA) neurons in the substantia nigra and loss of DA transmission in the striatum, thus making cell transplantation an effective treatment strategy. Here, we develop a cellular therapy based on induced pluripotent stem cell (iPSC)-derived midbrain organoids. By transplanting midbrain organoid cells into the striatum region of a 6-OHDA-lesioned PD mouse model, we found that the transplanted cells survived and highly efficiently differentiated into DA neurons. Further, using a dopamine sensor, we observed that the differentiated human DA neurons could efficiently release dopamine and were integrated into the neural network of the PD mice. Moreover, starting from four weeks after transplantation, the motor function of the transplanted mice could be significantly improved. Therefore, cell therapy based on iPSC-derived midbrain organoids can be a potential strategy for the clinical treatment of PD.

Although clinical research has revealed microglia-related inflammatory and immune responses in bipolar disorder (BD) patient brains, it remains unclear how microglia contribute to the pathogenesis of BD. Here, we demonstrated that Serinc2 is associated with susceptibility to BD and showed a reduced expression in BDII patient plasma, which correlated with the disease severity. Using induced pluripotent stem cell (iPSC) models of sporadic and familial BDII patients, we found that Serinc2 expression showed deficits in iPSC-derived microglia-like cells, resulting in decreased synaptic pruning. Further, combining the microglia-specific Serinc2-deficient mouse and iPSC-microglia models, we found that microglial Serinc2 deficits functioned through attenuating the synthesis of serine-related phospholipids in the plasma membrane, thus resulting in depression-like behavioral abnormalities in the animals. Finally, we showed that the Serinc2-dependent lipid deficits diminished microglial membrane CR3 formation to interrupted synaptic pruning signals from neurons. Therefore, our results indicated that Serinc2 deficits in microglia might contribute to the pathogenesis of BD.

Midbrain organoids provide an innovative cellular source for transplantation therapies of neurodegenerative diseases. Here, we present a protocol for midbrain organoid-derived cell transplantation into a Parkinson’s disease mouse model. We describe steps for midbrain organoid generation, single-cell suspension preparation, and cell transplantation. This approach is valuable for studying the efficacy of midbrain organoids as a potential cellular source for restoring motor function. For complete details on the use and execution of this protocol, please refer to Fu et al. ¹