Journal of Molecular Neuroscience最新文献

Glioblastoma (GBM) is a highly aggressive brain tumor with frequent recurrence, yet the molecular mechanisms driving recurrence remain poorly understood. Identifying recurrence-associated genes may improve prognosis and treatment strategies. We applied weighted gene co-expression network analysis (WGCNA) to transcriptomic data from IDH-wildtype histological GBM in the CGGA-693 (n = 190) and CGGA-325 (n = 111) cohorts to identify recurrence-associated genes. These genes were validated using RT-qPCR and single-cell RNA sequencing (scRNA-seq) datasets (GSE174554, GSE131928). Their associations with immune cell composition were analyzed. Finally, we evaluated 113 machine learning algorithms to develop a multi-gene predictive model for GBM recurrence, with model performance assessed using receiver operating characteristic (ROC) curves and confusion matrix analysis. We identified eight recurrence-associated genes (CERS2, EML2, FNBP1, ICOSLG, MFAP3L, NPC1, ROGDI, SLAIN1) that were significantly differentially expressed between primary and recurrent GBM. The scRNA-seq analysis revealed cell-type-specific expression patterns, with eight genes predominantly enriched in oligodendrocytes, malignant GBM subtypes, and immune cells. Immune cell deconvolution showed significant alterations in macrophage polarization and NK cell activation in recurrent GBM. Machine learning analysis demonstrated that random forest (RF) was the most effective model, achieving AUC values of 0.998, 0.968, and 0.998 in the training, CGGA-693 validation, and CGGA-325 validation cohorts, respectively, suggesting high predictive accuracy. This study identifies novel recurrence-associated molecular signatures and establishes a machine learning-based predictive model in IDH-wildtype histological GBM.

Multiple sclerosis (MS), an autoimmune condition of the central nervous system (CNS), can lead to demyelination and axonal degeneration in the brain and spinal cord, which can cause progressive neurologic disability. MS symptoms include dysautonomia and progressive decline in motor abilities. In this investigation, we performed an integrated bioinformatics and experimental approach to find the expression level and interaction of a novel long non-coding RNA (lncRNA), PAN3-AS1, in MS samples. Microarray analysis was performed by R Studio using GEOquery and limma packages. lncRNA-mRNA RNA interaction analysis was performed using the lncRRIsearch database. Pathway enrichment analysis was performed by KEGG and Reactome online software through the Enrichr database. Protein–protein interaction analysis was performed by STRING online software. Gene ontology (GO) analysis was performed by Enrichr database. Based on microarray analysis, lncRNA PAN3-AS1 has a significantly low expression in MS samples compared to the control (logFC − 1.2, adj. P. Val 0.03). qRT-PCR results approved bioinformatics analyses. ROC analysis revealed that PAN3-AS1 could be considered a potential diagnostic biomarker of MS. Based on lncRNA-mRNA interaction analysis, lncRNA PAN3-AS1 regulates the expression level of RPGR. RPGR and its protein interactome regulate the cilium assembly, chaperon-mediated autophagy, and microarray biogenesis. lncRNA PAN3-AS1, as a significant low-expressed lncRNA in MS samples, could be a potential diagnostic MS biomarker. PAN3-AS1 might regulate the expression level of cilium assembly and chaperon-mediated autophagy. Dysregulation of PAN3-AS1 might affect the expression of RPGR and its protein interactome.

Transfer RNAs (tRNAs) are small non-coding RNA molecules transcribed from tRNA genes. tRNAs cleaved into a diverse population tRNA fragments (tRFs) ranging in length from 18 to 40 nucleotides, they interact with RNA binding proteins and influence the stability and translation. Stress is one of the reasons for tRFs cleavage. In our study, we modeled oxidative stress conditions with hydrogen peroxide (H₂O₂) exposure and dealt with one of the frequently expressed tRF in the hippocampus region of the brain, which is tRF-Glu-CTC. For this purpose, neural stem cells (NSCs) were exposed to H₂O₂, and tRF-Glu-CTC levels were increased in various H₂O₂ concentrations. A decrease was seen in microtubule-associated protein 2 (MAP2) marker expression. To understand the H₂O₂ oxidative stress condition on the expression of tRNA fragments, 72 hpf zebrafish embryos exposed to different H₂O₂ concentrations, an increase in the level of tRF-Glu-CTC was observed in all concentrations of H₂O₂ compared to control. Subsequently, neurogenesis markers were figured out via Calb2a (calbindin 2a) in situ hybridization (ISH) and HuC/D immunofluorescence staining (IF) staining experiments. Under H₂O₂ exposure, a decline was observed in Calb2a and HuC/D markers. To understand the inhibitory role of tRF-Glu-CTC on neurogenesis, NSCs were transfected via tRF-Glu-CTC inhibitor, and neurogenesis markers (ßIII-tubulin, MAP2, and GFAP) were determined with qRT-PCR and IF staining. tRF-Glu-CTC inhibitor reversed the diminished neuronal markers expression under the exposure of H₂O₂. Gene Ontology (GO) enrichment analysis showed us that targets of tRF-Glu-CTC are generally related to neuronal function and synaptic processes.

This study investigates the neuroprotective effects of fucoxanthinol (FXL) against the toxic activities of two compounds known to induce neurotoxic effects in humans and animals. MPTP (1-methyl- 4-phenyl- 1,2,3,6-tetrahydropyridine) induces Parkinson’s disease (PD)-like phenotypes by inhibiting mitochondrial complex I in dopaminergic neurons. Chlorpyrifos (CPF), another neurotoxic agent, is associated with acute and long-term neurotoxicity primarily through acetylcholinesterase (AChE) inhibition. FXL demonstrated the ability to reverse the neurotoxic effects of CPF and MPTP in SH-SY5Y dopaminergic neuronal cell models. Treatment with FXL enhances mitochondrial function in SH-SY5Y cells exposed to CPF and MPTP, as demonstrated by increased levels of Adenosine triphosphate (ATP), mitochondrial membrane potential (MMP), mitochondrial complexes activities, and oxygen consumption rates, pyruvate dehydrogenase (PDH) activities, and mitophagy pathways. This improvement highlights FXL’s ability to counteract the mitochondrial dysfunction induced by these neurotoxic agents. Additionally, FXL reduces oxidative damage and enhances cell viability. At the molecular level, the neuroprotective effects were also associated with the modulation of apoptotic cell markers, including Bcl- 2 and the oxidative damage markers. Molecular docking data further support the outcomes of our in vitro studies. Multivariable analysis highlights the neuroprotective effects of FXL. These findings indicate the potential of FXL to mitigate CPF- and MPTP-induced neurotoxicity, suggesting its promise as a therapeutic agent for managing neuronal damage observe in PD.

Fragile X syndrome is the most common inherited form of intellectual disability and is caused by the transcriptional silencing of the Fmr1 gene and the lack of fragile X messenger ribonucleoprotein (FMRP). FMRP is an RNA-binding protein that regulates the synthesis of synaptic proteins which are essential for proper brain function. Although circuit hyperexcitability is a hallmark of fragile X syndrome (FXS), the cell-autonomous effects of FMRP deficiency remain poorly understood. In this work, we investigated the functional consequences of the absence of FMRP on neuronal morphology and on ionotropic glutamate receptor surface distribution, using primary cultures of mice hippocampal neurons isolated from wild-type (WT) and Fmr1 knock-out (KO) pups. MAP2 staining of Fmr1 KO neurons showed a decrease in total dendritic length and complexity of the dendritic tree, accompanied by an increase in soma size compared to WT neurons. Moreover, immunolabelling of surface glutamate receptors performed under non-permeabilising conditions showed that Fmr1 KO neurons presented a higher content of synaptic surface GluN2A and a lower content of GluN2B subunits of NMDA receptors, while GluA1 and GluA2 distribution remained unchanged. Finally, multielectrode array data showed that Fmr1 KO neurons presented reduced spontaneous activity compared to control neurons. These data support the hypothesis that at the cellular level, Fmr1 KO hippocampal neurons are less excitable due to altered input processing, driven by structural defects and altered GluN2A expression in the synaptic plasma membrane.

Thyroid hormone receptor interactor 12 (TRIP12; MIM #617,752) is an autosomal dominant hereditary disorder involved in the ubiquitin fusion degradation pathway and the regulation of DNA damage-induced chromatin ubiquitination. Positioned on chromosome 2 at position 2q36.3, TRIP12 is a member of the E3 ubiquitin ligase family. This gene plays a vital role in proteasomal degradation by catalyzing substrate ubiquitination and regulating processes such as cell cycle progression, DNA damage repair, and chromatin remodeling. Mutations in TRIP12 can result in intellectual disability (ID), Clark-Baraitser syndrome, and various physical and behavioral abnormalities. The proband, a 32-year-old male, exhibited intellectual disability, delayed speech, and behavioral abnormalities without autistic spectrum disorders. The novel TRIP12 variant was detected through WES and validated by Sanger sequencing in affected family members. In silico tools predicted the deleterious effect of the variant, and protein modeling indicated significant structural changes. RT-qPCR demonstrated increased TRIP12 mRNA levels, suggesting a compensatory mechanism for decreased protein stability. This study examines the role of the TRIP12 gene in the ubiquitin pathway and associated pathologies such as intellectual disability and developmental delay.

Alzheimer’s disease (AD) is the most prevalent form of dementia, significantly contributing to the global health burden. The progressive accumulation of amyloid-beta (Aβ) plaques and tau tangles triggers neuroinflammation, oxidative stress, and neuronal damage, highlighting the critical need for effective clearance mechanisms. Recent research has identified low-density lipoprotein receptor-related protein 1 (LRP1) as a key factor in the regulation of Aβ clearance, neuroinflammation, and blood–brain barrier integrity, particularly in relation to the liver-brain axis. This review provides a comprehensive examination of the role of LRP1 in AD, focusing on its expression in the brain and liver, its contribution to Aβ metabolism, and its potential as a therapeutic target. Using a systematic literature review, LRP1’s multifaceted roles across various biological processes were explored, including its involvement in Aβ transport, clearance via the liver, and modulation of neuroinflammation. Additionally, the impact of physical exercise, pharmacological interventions, and dietary factors on LRP1 expression levels was investigated, elucidating how these approaches may enhance Aβ clearance. The findings demonstrate that LRP1 expression decreases progressively as AD advances, and that augmenting LRP1 activity—particularly through exercise and drug therapies—can improve Aβ clearance and reduce neuroinflammatory responses. Furthermore, LRP1’s involvement in the liver-brain axis reveals its broader systemic role in AD pathology. In conclusion, targeting LRP1 offers a promising avenue for AD prevention and treatment, providing new insights into the therapeutic potential of enhancing Aβ clearance pathways through the liver-brain axis.

Autism spectrum disorders (ASD) are characterized by clinical heterogeneity and may be associated with cerebral folate deficiency (CFD). Among the causes, folate receptor alpha autoantibodies (FRAA) and variants of the SLC19A1 gene are commonly highlighted. The aim of this study was to analyze the rs1051266 variant of the SLC19A1 gene in patients with ASD and CFD and to determine its relationship with clinical and laboratory parameters. The study included 227 children with ASD, 156 of whom had CFD. FRAA detection, genotyping of the rs1051266 variant, and folate metabolism marker measurement (homocysteine, vitamins B9, B12, B6) were performed. FRAA binding was detected in 39.2% of ASD patients, blocking FRAA in 3.5%, and a specific soluble folate receptor in 13.2%. The 80GA genotype was the most common (46.3%), and homocysteine levels tended to be moderately elevated (upper quartile – 7.0). Significant correlations were found between homocysteine levels and vitamins B9, B12, and B6 (p < 0.05) and between verbal impairments and vitamin B12 (p = 0.043). In ASD and CFD patients, the 80GG genotype was more frequent (p = 0.03) and vitamin B12 levels were elevated (p = 0.021). In the ASD group, correlations were found between the 80AA genotype and demyelination (p = 0.020) and between homocysteine levels and demyelination (p = 0.042). In conclusion, the rs1051266 variant of the SLC19A1 gene modifies the clinical course of ASD. Patients with ASD and CFD exhibited high variability in folate metabolism markers. These findings underline the need for further research on folate transport genetics for personalized prevention and treatment strategies for ASD and CFD.

The function of CD73 (Cluster of Differentiation 73), an enzyme involved in the formation of adenosine (ADO), in the development of glioblastomas has been demonstrated. Indeed, ADO helps tumor angiogenesis by stimulating endothelial cell migration, proliferation, and tube formation. However, the details of the molecular mechanisms are not yet fully understood. Given the importance of angiogenesis in cancer progression, invasion, and metastasis, this study aimed to investigate how the inhibition of CD73 by adenosine-5′-(α, β-methylene) diphosphate (APCP) affects the angiogenesis process of experimental orthotopic glioblastoma at mRNAs, microRNAs, and protein levels. According to the real-time-polymerase chain reaction (RT-PCR) results, inhibition of CD73 decreased the angiogenesis of glioblastoma by reducing the expression of vascular endothelial growth factor (VEGF) and hypoxia-inducible factor 1-alpha (HIF-1α) by ****P < 0.0001 and **P < 0.01, respectively. Furthermore, immunohistochemical staining showed that this treatment protocol attenuated the expression of VEGF and CD31. Moreover, APCP treatment significantly increased miR-16 expression in glioblastoma model rats by P < 0.001, but no significant change in miR-29A expression was observed. The results showed that the treatment did not lead to systemic damage or significant weight loss. Our results suggest that inhibition of CD73 may reduce the formation of new tumor vessels by inhibiting the VEGF, HIF-1α, and CD31 in this process. Therefore, CD73 may be a practical target and provide new opportunities to improve the treatment of malignant brain tumors.