Journal of Molecular Neuroscience最新文献

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.

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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.

Insomnia, a common complication following stroke, significantly impairs patients’ clinical outcomes. Electroacupuncture (EA), an advanced acupuncture technique, has demonstrated efficacy in alleviating insomnia symptoms. Agomelatine (AT), a melatonin receptor agonist, is widely utilized for depression management. This study aimed to evaluate the therapeutic effects of combined EA + AT therapy for post-stroke insomnia. A total of 120 stroke-related insomnia patients were randomly assigned to three intervention groups (n = 40 each): EA therapy, AT treatment, and EA + AT combination therapy. Sleep efficiency and cognitive function were comprehensively assessed using the Cardiopulmonary Coupling-based sleep quality evaluation system, Montreal Cognitive Assessment (MoCA), and National Institutes of Health Stroke Scale (NIHSS). The results revealed that all three interventions significantly enhanced sleep efficiency (EA: 78.23 ± 4.19; AT: 75, 5; EA + AT: 80.97 ± 4.21) and MoCA scores (EA: 24, 2; AT: 24, 2; EA + AT: 27, 2), with the combination therapy showing superior effectiveness. Similarly, NIHSS scores exhibited marked reduction across all treatment groups (EA: 6, 2; AT: 7, 2), particularly in the EA + AT combination cohort (EA + AT: 4, 3). Notably, post-treatment analysis revealed significant positive correlations between sleep efficiency and MoCA scores in all groups, with the strongest correlation observed in the AT group (r = 0.87). These findings demonstrate that EA + AT combination therapy outperforms monotherapies in treating post-stroke insomnia. In conclusion, this study establishes EA + AT as an effective intervention for improving both sleep quality and cognitive function in stroke-related insomnia patients, offering a promising therapeutic strategy for this clinical condition.

Diabetic nephropathy (DN) is characterized by nephron degeneration induced by hyperglycemia, driven by complex interactions between glucose metabolism dysregulation and immune microenvironment dynamics. This study employed machine learning and bioinformatics techniques to investigate the role of finerenone, a novel nonsteroidal mineralocorticoid receptor antagonist, in modulating immune dysregulation associated with DN through targeted intervention in PANoptosis-related networks. Using machine learning algorithms, five key PANoptosis-associated genes (CASP3, FLT3, KDR, HIF1A, and MMP2) were identified, and a diagnostic model incorporating these biomarkers demonstrated high efficacy in distinguishing patients with DN from controls. These genes were strongly correlated with immune cell infiltration, particularly mast cells, M2 macrophages, and B lymphocytes. KEGG and GSVA enrichment analyses highlighted significant pathway enrichment in PI3K-Akt signaling and glycosphingolipid biosynthesis (lacto and neolacto series). These results suggest that finerenone mitigates DN-related immune disruptions by modulating PANoptosis-linked gene expression, thereby influencing PI3K-Akt signaling and glycosphingolipid biosynthesis in mast cells, M2 macrophages, and B cells. This study provides new insights into potential therapeutic targets and pharmacological evidence for precision immunomodulation in DN treatment.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive motor neuron degeneration and a median survival of 3–5 years post-diagnosis. While the etiology of ALS remains elusive, mutations in SOD1, encoding the Cu/Zn superoxide dismutase enzyme, are strongly associated with familial ALS (fALS). These mutations promote a toxic gain-of-function, primarily through SOD1 misfolding and aggregation. We systematically assessed 244 SOD1 missense mutations using a multi-tiered computational framework encompassing structural, functional, and pathogenic predictors. Sequence-based predictors (SIFT, PolyPhen-2, FATHMM) and structure-guided tools (mCSM, PremPS, DynaMut2) identified 79 destabilizing mutations, 64 of which were classified as pathogenic by phenotype predictors (PhD-SNP, SNPs&GO, MutPred2). Twelve mutations resided in evolutionarily conserved regions, with eight (D84N, G73C, H72Y, P67A, P67R, P67S, R144G, S60I) exhibiting pronounced aggregation propensity via SODA analysis. Notably, H72Y disrupts a zinc-binding residue critical for structural integrity and catalysis. Protein–protein interaction networks linked SOD1 to ALS-associated pathways, highlighting its involvement in oxidative stress and protein homeostasis. Our integrative approach highlights the power of computational genomics in unraveling mutation-driven SOD1 dysfunction, offering mechanistic insights into ALS pathogenesis and guiding therapeutic strategies focused on aggregation-prone variants.

The CANT1 gene, encoding a nucleotidase linked to calcium signaling, is crucial for spinal development, with its deficiency causing skeletal developmental issues. However, the relationship between CANT1 and scoliosis remains unclear. This study aims to explore the role of CANT1 in scoliosis from a genetic perspective and its potential as a therapeutic target. This study employed a multi-method approach, including Mendelian Randomization (MR) analysis, colocalization analysis, mediation analysis, enrichment analysis, PPI network construction, and molecular docking. Using eQTL and pQTL databases, the Inverse Variance Weighted (IVW) method identified key genes associated with scoliosis. Colocalization analysis pinpointed genes with strong causal links to scoliosis. Mediation analysis assessed the impact of CANT1 methylation, immune cells, inflammatory factors, and plasma metabolites on scoliosis. Enrichment analysis identified biological pathways enriched in scoliosis-related genes. The PPI network was constructed using the STRING database, and CANT1 expression in bone marrow and skeletal muscle was analyzed via the Human Protein Atlas. Potential therapeutic compounds were identified through the DSigDB database and validated by molecular docking. We identified 94 key genes associated with scoliosis, primarily involved in purine ribonucleotide metabolism. Colocalization analysis provided strong evidence linking CANT1 to scoliosis. Further analysis revealed that methylation sites, immune cells, inflammatory factors, and plasma metabolites related to CANT1 may play roles in scoliosis pathogenesis. The regulatory expression of CANT1 was examined using the STRING database and the Human Protein Atlas. Six candidate compounds with favorable binding affinity to CANT1 were identified through DSigDB and molecular docking. This study offers new insights into the pathogenesis of scoliosis and highlights CANT1 as a potential therapeutic target. CANT1 may influence scoliosis development through multiple pathways, including methylation, immune cells, inflammatory factors, and plasma metabolites. Further experimental validation is needed to confirm these findings and explore the therapeutic potential of the identified compounds.