Qiang Liu

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.

Sex differences in obesity are well recognized; however, the identification of sex-specific obesity genes and the mechanisms through which they affect obesity development remain elusive. Here, we identify a germ-cell-specific gene C2orf74, whose expression is responsive to high-fat diet (HFD) and promotes HFD-induced obesity in male mice by restraining lipolysis and limiting the browning of white adipocytes through suppression of androgen receptor signaling, but not in females. Additionally, C2orf74's expression increases with aging, contributing to aging-related obesity and metabolic comorbidities in chow-fed male mice. We demonstrate that C2orf74 is an ER-residing transmembrane protein that anchors and stabilizes dolichol phosphate mannose synthase 1 (Dpm1) on the ER membrane, facilitating Dpm1-mediated glycosylation and secretion of Bpifa3 from germ cells. As a paracrine regulator, Bpifa3 transcriptionally suppresses the expression of testosterone biosynthesis enzymes in Leydig cells. Therapeutically, we demonstrate that antisense oligonucleotide (ASO) targeting C2orf74 protects male mice from HFD-induced obesity. Thus, our study defines a role for germ-Leydig cell crosstalk, mediated by C2orf74, in the white adipocytes browning in both age-associated and diet-induced obesity.

Transfer RNA-derived small RNAs (tsRNAs), a class of non-coding RNAs derived from precursor or mature tRNAs, are now recognized as critical regulators in response to cellular stress. tsRNAs exhibit differential expression during brain aging and in age-related neurodegenerative disorders such as Alzheimer’s disease (AD), suggesting their involvement in the molecular processes underlying neuronal aging and degeneration. This article summarizes recent advances in our understanding of tsRNA biogenesis, classification, and function, emphasizing their regulatory role in brain aging and AD pathology. We also highlight the diagnostic and therapeutic implications of tsRNAs and discuss future directions for exploring their mechanistic and clinical relevance.

The nucleolus is a dynamic, non-membrane-bound nuclear organelle organized into fibrillar and granular components, serving as a central hub for ribosome biogenesis, stress responses, and cell cycle regulation. In brain aging and Alzheimer’s disease (AD), it undergoes marked structural and functional alterations. Aging brains commonly exhibit cognitive decline, whereas AD is characterized by neuronal loss and biochemical abnormalities, including extracellular amyloid-beta plaques and tau hyperphosphorylation. Mounting evidence indicates that nucleolar alterations—such as impaired ribosome biogenesis, disrupted proteostasis, and activation of nucleolar stress pathways—occur early in AD pathogenesis. This review summarizes current understanding of nucleolar function, highlights its dysfunction in aging and AD, and discusses its potential as a therapeutic target.

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.