Juan Zhang

Cerebral ischemia-reperfusion induces myelin injury, resulting in cognitive impairment. Efficient clearance of myelin debris is important for neural repair. The E3 ubiquitin ligase Ring1 (RING finger protein 1) participates in ubiquitin signaling and gene expression regulation, However, whether Ring1 ameliorates cerebral ischemia–reperfusion injury-induced cognitive impairment by promoting microglial post-phagocytic myelin debris processing remains unknown. In this study, we employed a hemorrhagic shock and reperfusion model, a hippocampal myelin debris injection model, and an in vitro microglia–myelin debris co-culture model to simulate cerebral ischemia–reperfusion injury, and combined these models with proteomic and transcriptomic analyses and Ring1 gain- and loss-of-function approaches. Hemorrhagic shock and reperfusion induced hippocampal myelin injury and cognitive dysfunction, while hippocampal administration of myelin debris further impaired cognition. Transcriptomic analysis identified Ring1 as a candidate regulator associated with postphagocytic myelin debris processing. Ring1 overexpression alleviated cognitive deficits and hippocampal myelin injury and restored mitochondrial DNA-encoded gene expression and adenosine triphosphate levels after hemorrhagic shock and reperfusion. In contrast, Ring1 knockdown in the microglia–myelin debris co-culture model reduced mitochondrial DNAencoded gene expression and adenosine triphosphate levels and delayed post-phagocytic myelin debris processing. Mechanistically, Ring1 interacted with mitochondrial transcription factor B2, with K27-linked ubiquitin signals detected in Ring1- and mitochondrial transcription factor B2-containing immunocomplexes. Ring1 depletion reduced mitochondrial transcription factor B2-associated K27-linked ubiquitin signaling, mitochondrial DNA-encoded gene expression, adenosine triphosphate levels, and post-phagocytic myelin debris processing. Collectively, our findings suggest that Ring1 attenuates hemorrhagic shock and reperfusion-related cognitive impairment by promoting microglial post-phagocytic myelin debris processing through mitochondrial transcription factor B2-associated K27-linked ubiquitin signaling and mitochondrial regulation.

During brain development, neural progenitor cells (NPCs) undergo rapid division, necessitating efficient ribosomal biogenesis for proliferation. Yet, the regulatory mechanisms remain largely elusive. Here, we report that the DNA binding protein Kin17 exhibits development-dependent expression and plays a vital role in embryonic development. Complete loss of Kin17 in mice leads to embryonic lethality, while Kin17 depletion specifically in NPCs allows embryonic survival but results in reduced brain size and cortical lamination defects. Our findings demonstrate that these cortical malformation stems from impaired NPC proliferation and differentiation. Mechanistically, we show that Kin17 binds to the promoter region of rDNA, sequentially recruiting NCL and Polr1a, thereby promoting rDNA transcription. Consequently, Kin17 facilitates ribosome biogenesis and protein translation in NPCs. This study underscores a critical role of Kin17 in promoting rDNA transcription and ribosomal biogenesis in NPCs during brain development, which is essential for proper cortical lamination.

The entorhinal cortex (EC)-hippocampal (HPC) circuit is particularly vulnerable to Alzheimer’s disease (AD) pathology, yet the underlying molecular mechanisms remain unclear. By employing the high-depth sequencing strategy Smart-seq2, we tracked gene expression changes across various neuron types within this circuit at different stages of AD pathology. We observed a decrease in the extent of gene expression changes in AD versus wild-type (WT) mice as the disease advanced. Functionally, we demonstrate that both mitochondrial and ribosomal pathways were increasingly activated, while neuronal pathways were inhibited with AD progression. Our findings indicate that the reduction of EC-stellate cells disrupts Meg3-mediated energy metabolism, contributing to energy dysfunction in AD. Additionally, we identified GFAP-positive neurons as a distinct population of disease-associated neurons, exhibiting a loss of neuronal-like characteristics, alongside the emergence of glia- and stem-like features. The number of GFAP-positive neurons increased with AD progression, a trend consistently observed in both AD model mice and AD patients. In summary, this study identifies and characterizes GFAP-positive neurons as a novel subtype of disease-associated neurons in AD pathology, providing insights into their potential role in disease progression.

SFRS8, a member of the serine and arginine-rich (SR) protein family, functions as a splicing factor and is highly expressed in the brain. Despite its abundance, its specific role in the brain has remained unclear. Here, we show that SFRS8 is critical for maintaining normal synaptic protein levels and synaptic density. Mechanistically, SFRS8 binds to SF3B3, a key component of the U2 snRNP complex, to regulate alternative RNA splicing. Specifically, SFRS8 regulates the association of Psd95 pre-mRNA with the U2 snRNP complex and subsequent exon 18 skipping in Psd95, thereby controlling PSD95 protein levels. Knockdown of SFRS8 in the hippocampus reduces synaptic protein expression, decreases dendritic spine density, and impairs memory in mice. Consistent with these in vivo findings, SFRS8 depletion in cultured neurons also leads to lower synaptic protein levels and reduced synaptic density. Taken together, our results demonstrate that SFRS8 regulates memory function in mice by modulating the alternative splicing and expression of synaptic genes through its interaction with SF3B3, a core component of the U2 snRNP complex.

Cholesterol plays a crucial role in brain, where it is highly concentrated and tightly regulated to support normal brain functions. It serves as a vital component of cell membranes, ensuring their integrity, and acts as a key regulator of various brain processes. Dysregulation of cholesterol metabolism in the brain has been linked to impaired brain function and the onset of neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD). A significant advancement has been the identification of astrocyte-derived ApoE as a key regulator of de novo cholesterol biosynthesis in neurons, providing insights into how extracellular signals influence neuronal cholesterol levels. Additionally, the development of antibody-based therapies, particularly for AD, presents promising opportunities for therapeutic interventions. Despite significant research, the association between cholesterol and neurodegenerative diseases remains inconclusive. It is crucial to distinguish between plasma cholesterol and brain cholesterol, as these pools are relatively independent. This differentiation should be considered when evaluating statin-based treatment approaches. Assessing not only the total cholesterol content in the brain but also its distribution among different types of brain cells is essential. Establishing a causal link between changes in brain/plasma cholesterol levels and the onset of brain dysfunction/neurodegenerative diseases remains a key objective. Additionally, conducting cell-specific analyses of cholesterol homeostasis in various types of brain cells under pathological conditions will enhance our understanding of cholesterol metabolism in neurodegenerative diseases. Manipulating cholesterol levels to restore homeostasis may represent a novel approach for alleviating neurological symptom.

The nucleolus is a compartmentalized organelle in eukaryotic cells known to form during embryogenesis, yet how its layered architecture is transformed from homogenous precursor bodies is unclear, and any impacts of this formation on embryonic cell fate determination remain unknown. Here, we demonstrate that lncRNA LoNA tethers granular-component-enriched NPM1 to dense-fibrillar-component-enriched FBL and drives the formation of compartmentalized nucleolus via facilitating liquid–liquid phase separation of those two nucleolar proteins. Phenotypically, LoNA-deficient embryos show developmental arrest at the two-cell (2C) stage. Mechanistically, we demonstrate that LoNA deficiency leads to nucleolar formation failure, resulting in mislocalization and acetylation of NPM1 in the nucleoplasm. Acetylated NPM1 recruits and guides PRC2 complex to 2C genes, where PRC2 complex trimethylates H3K27, leading to transcriptional repression of these genes. Collectively, our findings reveal that lncRNA is required for the establishment of nucleolar structure, and this process has an impact on two-cell embryonic development via 2C transcriptional activation.