Journal of Molecular Neuroscience最新文献

Glioblastoma (GBM) represents one of the most aggressive brain tumors with a poor prognosis despite decades of research. Epigenetic regulation has emerged as a promising strategy for managing aggressive cancers, such as GBM, by modulating pro-tumorigenic gene expression. The role of pro-tumorigenic genes, such as oligodendrocyte transcription factor 2 (OLIG2), has been heavily associated with cancer progression and treatment resistance and is a potential target for GBM. The objective of this study is to analyze the effectiveness of various epigenetic regulators, including histone modifiers, DNA methylases, chromatin remodelers, and miRNAs, on OLIG2 expression, including the effectiveness of individual epigenetic regulators and their combinations. The effects of epigenetic regulators in GBM that are found in the literature were reviewed for their survival and co-expression with OLIG2. We found that KDM6B, BRG1, DNMT1, and HDAC2 were associated with significant co-expression with OLIG2 and decreased survival in GBM patients, reinforcing their suitability as targets. Additionally, miR-17-3p miRNAs associated with silencing OLIG2 as gene expression was downregulated in GBM. Additionally, this paper highlights the potential of combination therapies targeting multiple epigenetic pathways simultaneously. A kinase inhibitor (alisertib), together with JQ1, reduced the tumor growth of GBM cells in vivo more than either treatment alone, making combination therapies a promising solution.

Premature ovarian failure (POF) accelerates ovarian aging, leading to menstrual irregularities, reduced fertility, and decreased estrogen levels. Current hormone replacement therapy (HRT) cannot reverse the aging effects, highlighting the need for more targeted treatments. Genome-wide association studies (GWAS) and protein quantitative trait loci (pQTL) analyses can identify genetic variants and protein level changes associated with POF. Mendelian randomization (MR) evaluates the causal relationships between genetic variants and POF. pQTL analysis was conducted using plasma proteomics data from 54,219 participants and baseline cohort data of 34,557 individuals of European ancestry from the UK Biobank. GWAS data comprising 542 POF cases and 218,970 controls were obtained from the FinnGen database. MR analysis utilized inverse variance weighted (IVW), MR Egger, weighted median, and weighted mode methods. Colocalization analysis was performed using the “coloc” R package, and pathway enrichment analysis was conducted using the “clusterProfiler” package. Additionally, reverse MR analysis, molecular docking predictions, and summary data-based Mendelian randomization (SMR) analysis were performed. Finally, based on the scRNA-seq data of POF, analyses such as cell type annotation, gene set scoring, and cell–cell communication were performed. MR analysis identified significant causal relationships between specific proteins (BSG, CCL23, CTSC, FAP, IGSF21, LCN15, LILRB2, MUC16, PTN, SPINK1, TNFRSF1B, TNFRSF8, TNXB, and YJU2) and POF. Colocalization analysis indicated that key proteins (BSG, CCL23, FAP, and TNXB) share causal variants with POF traits. SMR analysis confirmed TNXB as a risk factor for POF. Finally, using the scRNA-seq data of POF, the expression of key gene sets was used to evaluate the scoring of different cell populations. Cell–cell communication analysis identified multiple communication pathways between high-scoring cell populations and other cell groups. The expression trend of key proteins was further verified by western blot assay. These findings are preliminary and require significant validation before clinical application. Combining pQTL and GWAS data, MR and colocalization analyses identified key proteins and genetic variants associated with POF, providing deeper insights into POF mechanisms and potential therapeutic targets.

Low-grade gliomas (LGGs) represent a complex and aggressive category of brain tumors. Despite recent advancements in molecular subtyping and characterization, the necessity to identify additional molecular subtypes and biomarkers remains. To delineate survival subtypes in LGG, we propose a deep learning (DL)-based multi-omics SurvivalNet (MOST) model. By integrating histological RNA-seq, miRNA-seq, and DNA methylation data obtained from The Cancer Genome Atlas (TCGA), we applied the MOST model to analyze data from 497 LGG patients. We employed consensus clustering to reveal heterogeneous subtypes, validated our findings using an internal validation set through a supervised classification algorithm, and further evaluated the robustness of our model in an independent external cohort. The DL-based MOST model identified two optimal patient subtypes with significant differences in survival (P = 3.07E − 16) and demonstrated a robust model fit (C = 0.92 ± 0.02). This multi-omics model was validated using external Chinese Glioma Genome Atlas (CCGA) datasets, including RNA-Seq (N = 497, C = 0.85), miRNA array (N = 89, C = 0.80), and DNA methylation (N = 89, C = 0.61). High-risk subcategories exhibited increased expression of the homeobox (HOX) family genes, regulation of cholesterol homeostasis, glycolysis, epithelial-mesenchymal transition pathway enrichment, and a high density of M2 macrophages. Our study utilized deep learning to identify multi-omics features associated with differential survival outcomes in patients with LGG. This work is anticipated to significantly enhance prognosis prediction for LGG due to its robustness within the cohorts.

Background

Neuroinvasive pathogens are capable of breaching the blood–brain barrier (BBB), and causing central nervous system infections. Although the response of human brain microvascular endothelial cells (hBMECs), the forefront cells of BBB has been extensively studied, the roles of astrocytes and pericytes in modulating BBB integrity during infection remain less defined.

Aims

The study aims for a meta-analysis of RNA-seq data to compare the transcriptional response of hBMECs alone and in co-culture with astrocytes and pericytes (BBB-spheroids) following infection with Neisseria meningitidis and Borrelia bavariensis. Subsequently, identifying the pathogen-specific gene signatures that regulates the signalling pathways associated with infection and BBB disruption.

Methods

Unique and shared differentially expressed genes (DEGs) of hBMECs and BBB-spheroids were identified and analysed for functional enrichment using DAVID. Protein–protein interaction networks were constructed and analysed in Cytoscape using MCODE and cytoHubba to identify infection-related hub genes.

Results

A large proportion of DEGs were unique to each BBB model during infection, 49% in Neisseria and 66% in Borrelia infection, whereas only 4.9% were shared. hBMECs predominantly expressed defence-related genes, whereas BBB-spheroids expressed genes linked to barrier function. Notably, IFIH1, IFIT1, IFIT3, ISG15, MX1, OAS1, and RSAD2 were identified as regulators of the BBB’s transcriptomic response to infection.

Conclusions

The meta-analysis highlights distinct yet complementary roles of endothelial cells and the supporting pericytes and astrocytes in BBB regulation to bacterial invasion. The identified hub genes may serve as key regulators of infection-driven inflammation and form potential diagnostic or prognostic targets.

Graphical Abstract

Sortilin, a type I transmembrane protein encoded by SORT1 and part of the VPS10-domain receptor family, is crucial for intracellular trafficking and APP processing in Alzheimer’s disease (AD). It promotes protective α-secretase cleavage to prevent Aβ formation and aids Aβ clearance. However, under certain conditions, sortilin can become neurotoxic, causing Aβ buildup, tau phosphorylation, protein misrouting, and apoptosis, which accelerate neuronal damage and cognitive decline. No longitudinal human studies have yet explored how plasma and CSF Aβ42 predict plasma sortilin across the AD spectrum or whether whole-brain volume mediates the relationship between plasma sortilin and cognitive impairment. This study aimed to clarify these relationships and assess plasma sortilin as an indicator of central and peripheral amyloid pathology in AD for future experimental research. The results showed that at baseline, CSF Aβ42 levels were significantly lower in mild cognitive impairment (MCI) and AD compared to controls, while plasma Aβ42 levels did not differ, and sortilin levels were significantly reduced in MCI versus controls but not between other groups. Over 12 months, plasma sortilin levels declined in cognitively normal (CN) individuals but increased in MCI and AD, plasma Aβ42 rose across all groups, and CSF Aβ42 decreased modestly, highlighting diagnosis-specific sortilin changes and differing plasma versus CSF Aβ42 dynamics. Solely in MCI, higher plasma and CSF Aβ42 independently predicted increased plasma sortilin levels over time, indicating both peripheral and central Aβ42 contribute to sortilin upregulation, but when both were elevated simultaneously, the sortilin increase was attenuated, suggesting a non-linear or compensatory response. At the 12-month time point, higher plasma sortilin levels were negatively associated with whole-brain volume in MCI. In contrast, higher plasma Aβ42 levels showed positive associations with whole-brain volume in both CN and MCI groups, while no such association was observed in AD. CSF Aβ42 was not significantly related to brain volume in any group. Notably, at the 12-month time point in MCI, higher plasma sortilin levels were associated with poorer cognitive performance indirectly via reduced whole-brain volume; this mediation effect was not observed in CN or AD groups. Thus, plasma and CSF Aβ42 levels predict plasma sortilin levels, which may contribute to brain volume reduction and subsequent cognitive impairment, highlighting sortilin as a potential mediator or early indicator of neurodegeneration in AD progression.

Kv2.1 channels, a subset of voltage-gated potassium channels, play critical roles in regulating cellular processes such as proliferation and apoptosis. While cannabidiol (CBD), a non-psychoactive phytocannabinoid, is known to modulate various ion channels, its specific effects on Kv2.1 channels remain largely unexplored. In this study, we investigated the influence of CBD on Kv2.1 channel activity and its impact on cell viability under both normal and stress conditions. To achieve stable Kv2.1 expression, HEK293 cells were transfected using the Sleeping Beauty transposon XB100 system. Puromycin (4 µg/mL) was used for selection over multiple passages. Cell viability and morphological changes were assessed using MTT assays and Giemsa staining under standard culture conditions (DMEM) and nutrient deprivation (ND) to simulate metabolic stress. CBD was applied in concentrations ranging from 3 to 3000 nM. Under standard conditions, CBD did not significantly affect cell viability during early exposure. However, under ND conditions, CBD-treated cells exhibited marked morphological deterioration and decreased viability, with these effects becoming more pronounced at higher CBD concentrations. Interestingly, Kv2.1-expressing cells showed improved baseline viability under ND, suggesting a protective role for the channel during metabolic stress. Electrophysiological analyses revealed that CBD inhibits Kv2.1 channel activity, primarily through enhanced channel inactivation. This inhibition increased cellular vulnerability to stress-induced damage. These findings reveal a dose-dependent interaction between CBD and Kv2.1 suggesting that Kv2.1 may be a relevant therapeutic target in pathological conditions such as tumor microenvironments, where cells experience oxidative stress and nutrient deprivation.

This study aimed to investigate the effects of a histamine-reducing diet on five developmental domains in autism spectrum disorder subjects and the impact of variants in the AOC1 and HNMT genes on the therapeutic outcomes. Four genetic variants (rs2052129, rs10156191, rs1049742, and rs11558538) in AOC1 and HNMT were genotyped in 400 Bulgarian children with ASD. Genotype and allele frequencies were compared to control data from the GnomAD database. Further analysis was conducted on 91 ASD subjects with elevated histamine who followed the histamine-reducing diet. Significant improvements were observed across all developmental domains measured by the DP-3 test, including physical, adaptive behavior, social-emotional, cognitive, and communication skills. Paired samples T-tests indicated statistically significant increases in all categories (p < 0.001), with physical scores increasing from 82.29 to 89.18, adaptive behavior from 72.68 to 81.35, social-emotional from 71.43 to 80.22, cognitive from 69.33 to 78.66, and communication from 67.36 to 77.54. Minor allele carriers exhibited lower mean improvements across each of the five developmental parameters compared to wild-type carriers, with mean reductions of 0.90 for rs2052129, 0.70 for rs10156191, 2.07 for rs1049742, and 1.94 for rs11558538. These findings highlight the potential role of histamine regulation in autism spectrum disorder, the impact of variants in the AOC1 and HNMT genes on the therapeutic outcome and suggest dietary management as a viable intervention to improve developmental outcomes.

Schizophrenia (SCZ) is a severe mental disorder that significantly impacts the social functioning of patients and can reduce their life expectancy and quality of life. However, the specific causes of SCZ remain unknown, and the evidence indicates that long noncoding RNAs (lncRNAs) play critical roles in its pathogenesis. Analyzing lncRNA expression in peripheral blood samples from patients could reveal the biological mechanisms underlying the disease and help in the identification of biomarkers for early diagnosis and treatment. This study utilized whole-transcriptome sequencing to analyze lncRNA expression in 5 SCZ patients and 5 healthy controls. We constructed lncRNA‒microRNA (miRNA) and miRNA‒messenger RNA (mRNA) interaction pairs and established a competing endogenous RNA (ceRNA) network. Additionally, a weighted gene coexpression network analysis (WGCNA) and lncRNA‒RNA binding protein (RBP) network construction were performed. The potential functions of the mRNAs were predicted using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. A total of 438 differentially expressed lncRNAs (DElncRNAs) were identified in patients with SCZ compared with controls, with 260 upregulated and 178 downregulated. The ceRNA network comprised 383 DElncRNAs, 304 miRNAs, and 1849 mRNAs. GO and KEGG analyses indicated that these genes are involved in pathways such as the HIF-1 signaling pathway and oxidative phosphorylation, both of which are relevant to SCZ. Based on the ceRNA network-derived mRNAs, WGCNA identified three disease-associated modules. Furthermore, interactions between RBPs and DElncRNAs may play a significant role in the pathophysiology of SCZ. This study identifies 438 dysregulated lncRNAs in SCZ, constructs a ceRNA network implicating HIF-1 signaling and oxidative phosphorylation pathways, and reveals disease-associated coexpression modules and RBP-lncRNA interactions, providing novel insights into SCZ pathogenesis and potential diagnostic biomarkers.

Schizophrenia, a severe neuropsychiatric disorder, is characterized by significant impairments in neurological function. The disease includes a spectrum of symptoms that are divided into four main categories: positive, negative, cognitive, and mood symptoms. In this study, 32 male Wistar rats, approximately 10 to 12 weeks old, were randomly separated into four groups: vehicle (saline), ketamine (30 mg/kg), aripiprazole (0.75 mg/kg), and risperidone (1 mg/kg). Twenty-four hours following the final ketamine or saline administration, social interaction test (SIT), open field test (OFT), novel object recognition (NOR), and elevated plus-maze (EPM) were performed on the animals. Hippocampal tissue was used for molecular analysis using Real-Time PCR technique. Behavioral tests revealed that both risperidone and aripiprazole reduced anxiety-like behaviors and enhanced cognitive discrimination. At the molecular level, hippocampal expression of DRD2 and HTR2A did not differ significantly across groups. However, the ketamine-treated group exhibited elevated AKT1 expression relative to the vehicle group, whereas risperidone administration downregulated AKT1 compared to the ketamine group. Notably, CACNA1C expression was upregulated in the aripiprazole group compared to both the ketamine and vehicle groups. The findings of this study showed that the antipsychotic drugs risperidone and aripiprazole have the ability to moderately alleviate cognitive deficits in rats. The results also indicated that this treatment may affect the gene expression of AKT1, and CACNA1C genes.

Graphical Abstract

Tay-Sachs disease (TSD) is a rare lysosomal storage disorder marked by the progressive buildup of GM2 in the central nervous system (CNS). This condition arises from mutations in the HEXA gene, which encodes the α subunit of the enzyme β-hexosaminidase A. A newly developed mouse model for early-onset TSD (Hexa-/-Neu3-/-) exhibited signs of neurodegeneration and neuroinflammation, evidenced by elevated levels of pro-inflammatory cytokines and chemokines, as well as significant astrogliosis and microgliosis. Identifying disease-specific microRNAs (miRNAs) may aid the development of targeted therapies. Although previous small-scale studies have investigated miRNA expression in some regions of GM2 gangliosidosis mouse models, thorough profiling of miRNAs in this innovative TSD model remains to be done. In this study, we employed next-generation sequencing to analyze the complete miRNA profile of neuroglial cells from Hexa-/-Neu3-/- mice. By comparing KEGG and Reactome pathways associated with neurodegeneration, neuroinflammation, and sphingolipid metabolism in Hexa-/-Neu3-/- neuroglial cells, we discovered new microRNAs and their targets related to the pathophysiology of GM2 gangliosidosis. For the first time, our findings showed that miR-708-5p, miR-672-5p, miR-204-5p, miR-335-5p, and miR-296-3p were upregulated, while miR-10 b-5p, miR-615-3p, miR-196a-5p, miR-214-5p, and miR-199a-5p were downregulated in Hexa-/-Neu3-/- neuroglial cells in comparison to age-matched wild-type (WT). These specific changes in miRNA expression deepen our understanding of the disease's neuropathological characteristics in Hexa-/-Neu3-/- mice. Our study suggests that miRNA-based therapeutic strategies may improve clinical outcomes for TSD patients.