Molecular Neurobiology最新文献

Spinal cord injury (SCI) is a significant health concern, as it presently has no effective treatment in the clinical setting. Inflammation is a key player in the pathophysiological process of SCI, with a number of studies evidencing that the inhibition of the NF-κB signaling pathway may impede the inflammatory response and improve SCI. OTULIN, as a de-ubiquitination enzyme, the most notable is its anti-inflammatory effect. OTULIN can inhibit the NF-κB signaling pathway to suppress the inflammatory reaction via de-ubiquitination. In addition, OTULIN may promote vascular regeneration through the Wnt/β-catenin pathway in the wake of SCI. In this review, we analyze the structure and physiological function of OTULIN, along with both NF-κB and Wnt/β-catenin signaling pathways. Furthermore, we examine the significant role of OTULIN in SCI through its impairment of the NF-κB signaling pathway, which could open the possibility of it being a novel interventional target for the condition.

Alzheimer's disease (AD) is a common age-associated progressive neurodegenerative disorder that is implicated in the aberrant regulation of numerous circular RNAs (circRNAs). Here, we reported that circ-Bptf, a conserved circRNA derived from the Bptf gene, showed an age-dependent decrease in the hippocampus of APP/PS1 mice. Overexpression of circ-Bptf significantly reversed dendritic spine loss and learning and memory impairment in APP/PS1 mice. Moreover, we found that circ-Bptf was predominantly localized to the cytoplasm and upregulated p62 expression by binding to miR-138-5p. Furthermore, the miR-138-5p mimics reversed the decreased expression of p62 induced by the silencing of circ-Bptf. Together, our findings suggested that circ-Bptf ameliorated learning and memory impairments via the miR-138-5p/p62 axis in APP/PS1 mice. It may act as a potential player in AD pathogenesis and therapy.

This study investigates the role and molecular mechanism of EZH2 in glioma cell proliferation, invasion, and migration. EZH2, miR-142-3p, lncRNA KCNQ1OT1, LIN28B, and HMGB3 expressions in glioma tissues and cells were determined using qRT-PCR or Western blot, followed by CCK-8 assay detection of cell viability, Transwell detection of invasion and migration, ChIP analysis of the enrichment of EZH2 and H3K27me3 on miR-142-3p promoter, dual-luciferase reporter assay and RIP validation of the binding of miR-142-3p-KCNQ1OT1 and KCNQ1OT1-LIN28B, and actinomycin D detection of KCNQ1OT1 and HMGB3 mRNA stability. A nude mouse xenograft model and a lung metastasis model were established. EZH2, KCNQ1OT1, LIN28B, and HMGB3 were highly expressed while miR-142-3p was poorly expressed in gliomas. EZH2 silencing restrained glioma cell proliferation, invasion, and migration. EZH2 repressed miR-142-3p expression by elevating the H3K27me3 level. miR-142-3p targeted KCNQ1OT1 expression, and KCNQ1OT1 bound to LIN28B to stabilize HMGB3 mRNA, thereby promoting its protein expression. EZH2 silencing depressed tumor growth and metastasis in nude mice via the miR-142-3p/KCNQ1OT1/HMGB3 axis. In conclusion, EZH2 curbed miR-142-3p expression, thereby relieving the inhibition of KCNQ1OT1 expression by miR-142-3p, enhancing the binding of KCNQ1OT1 to LIN28B, elevating HMGB3 expression, and ultimately accelerating glioma cell proliferation, invasion, and migration.

Cognitive impairment (CI) is a common complication of the non-motor symptoms in Parkinson's disease (PD), including PD with mild cognitive impairment (PD-MCI) and PD dementia. Recent studies reported the oral dysbiosis in PD and CI, respectively. Porphyromonas gingivalis (P. gingivalis), a pathogen of oral dysbiosis, plays an important role in PD, whose lysine-gingipain (Kgp) could lead to AD-type pathologies. No previous study investigated the composition of oral microbiota and role of P. gingivalis in PD-MCI. This study aimed to investigate the differences of oral microbiota composition, P. gingivalis copy number, and Kgp genotypes among PD-MCI, PD with normal cognition (PD-NC) and periodontal status-matched control (PC) groups. The oral bacteria composition, the copy number of P. gingivalis, and the Kgp genotypes in gingival crevicular fluid from PD-MCI, PD-NC, and PC were analyzed using 16S ribosomal RNA sequencing, quantitative real-time PCR, and MseI restriction. We found that the structures of oral microbiota in PD-MCI group were significantly different compared to that in PD-NC and PC group. The relative abundances of Prevotella, Lactobacillus, Megasphaera, Atopobium, and Howardella were negatively correlated with cognitive score. Moreover, there was a significant difference of Kgp genotypes among the three groups. The predominant Kgp genotypes of P. gingivalis in the PD-MCI group were primarily Kgp II, whereas in the PD-NC group, it was mainly Kgp I. The Kgp II correlated with lower MMSE and MoCA scores, which suggested that Kgp genotypes II is related to cognitive impairment in PD.

Dysfunction of cerebral endothelial cells (CECs) has been implicated in the pathology of Alzheimer's disease (AD). Despite evidence showing cytotoxic effects of oligomeric amyloid-β (oAβ) and Tau (oTau) in the central nervous system, their direct effects on CECs have not been fully investigated. In this study, we examined the direct effects of oAβ, oTau, and their combination on cell adhesion properties and inflammatory responses in CECs. We found that both oAβ and oTau increased cell stiffness, as well as the p-selectin/Sialyl-Lewis^X (sLe^X) bonding-mediated membrane tether force and probability of adhesion in CECs. Consistent with these biomechanical alterations, treatments with oAβ or oTau also increased actin polymerization and the expression of p-selectin at the cell surface. These toxic oligomeric peptides also triggered inflammatory responses, including upregulations of p-NF-kB p65, IL-1β, and TNF-α. In addition, they rapidly activated the RhoA/ROCK pathway. These biochemical and biomechanical changes were further enhanced by the treatment with the combination of oAβ and oTau, which were significantly suppressed by Fasudil, a specific inhibitor for the RhoA/ROCK pathway. In conclusion, our data suggest that oAβ, oTau, and their combination triggered subcellular mechanical alterations and inflammatory responses in CECs through the RhoA/ROCK pathway.

Blood-brain barrier (BBB) is a distinguishing checkpoint that segregates peripheral organs from neural compartment. It protects the central nervous system from harmful ambush of antigens and pathogens. Owing to such explicit selectivity, the BBB hinders passage of various neuroprotective drug molecules that escalates into poor attainability of neuroprotective agents towards the brain. However, few molecules can surpass the BBB and gain access in the brain parenchyma by exploiting surface transporters and receptors. For successful development of brain-targeted therapy, understanding of BBB transporters and receptors is crucial. This review focuses on the transporter and receptor-based mechanistic pathway that can be manoeuvred for better comprehension of reciprocity of receptors and nanotechnological vehicle delivery. Nanotechnology has emerged as one of the expedient noninvasive approaches for brain targeting via manipulating the hurdle of the BBB. Various nanovehicles are being reported for brain-targeted delivery such as nanoparticles, nanocrystals, nanoemulsion, nanolipid carriers, liposomes and other nanovesicles. Nanotechnology-aided brain targeting can be a strategic approach to circumvent the BBB without altering the inherent nature of the BBB.

Spinal cord injury (SCI) is a serious disease without effective therapeutic strategies. To identify the potential treatments for SCI, it is extremely important to explore the underlying mechanism. Current studies demonstrate that anoikis might play an important role in SCI. In this study, we aimed to identify the key anoikis-related genes (ARGs) providing therapeutic targets for SCI. The mRNA expression matrix of GSE45006 was downloaded from the Gene Expression Omnibus (GEO) database, and the ARGs were downloaded from the Molecular Signatures Database (MSigDB database). Then, the potential differentially expressed ARGs were identified. Next, correlation analysis, gene ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, and protein-protein interaction (PPI) analysis were employed for the differentially expressed ARGs. Moreover, miRNA-gene networks were constructed by the hub ARGs. Finally, RNA expression of the top ten hub ARGs was validated in the SCI cell model and rat SCI model. A total of 27 common differentially expressed ARGs were identified at different time points (1, 3, 7, and 14 days) following SCI. The GO and KEGG enrichment analysis of these ARGs indicated several enriched terms related to proliferation, cell cycle, and apoptotic process. The PPI results revealed that most of the ARGs interacted with each other. Ten hub ARGs were further screened, and all the 10 genes were validated in the SCI cell model. In the rat model, only seven genes were validated eventually. We identified 27 differentially expressed ARGs of the SCI through bioinformatic analysis. Seven real hub ARGs (CCND1, FN1, IGF1, MYC, STAT3, TGFB1, and TP53) were identified eventually. These results may expand our understanding of SCI and contribute to the exploration of potential SCI targets.

The neurodegenerative disorder known as Parkinson's disease (PD) affects many people. The objective of this investigation was to examine the relationship between immune system infiltration, ATP-binding cassette transporter subfamily A member 7 (ABCA7) and TBL2 as well as potential therapeutic targets for the identification of PD associated to endoplasmic reticulum (ER) stress. First, we obtained PD data through GEO and divided it into two sets: a training set (GSE8397) plus a set for validation (GSE7621). Functional enrichment analysis was performed on a set of DEGs that overlapped with genes involved in endoplasmic reticulum stress. To identify genes of PD linked with endoplasmic reticulum stress, we employed random forest (RF) along with the least absolute shrinkage and selection operator (LASSO) logistic regression. Spearman's rank correlation analysis was then used to find associations among diagnostic markers with immune cell penetration. A grand total of 2 stress-related endoplasmic reticulum signature transcripts were identified. ABCA7 and TBL2 were shown to have diagnostic potential for PD and immune infiltrating cells have a role in the etiology of the disease. Additionally, resting CD4 memory, plasma cells, and NK cells overall exhibited positive associations with ABCA7, whereas triggered macrophages, T cells with active CD4 memory, activating NK cells, T cells with activated CD4 naive, engaged NK cells, and neutrophils all had adverse interactions with ABCA7. Overall, ABCA7 together with TBL2 have diagnostic utility for PD, and several types of immune cells, especially macrophages, may be involved in the development and progression of the disease.

Subarachnoid hemorrhage (SAH) is a neurological emergency that can lead to fatal outcomes. It occurs when bleeding happens in the subarachnoid space, a small gap between the arachnoid and pia mater. This condition results from the rupture of diseased or damaged blood vessels at the brain's base or surface. This study combined various omics approaches with Mendelian randomization analysis, including MR-IVW, MR Egger, MR weight median, and MR weight mode, to generate preliminary results. It also employed reverse Mendelian randomization, treating SAH as the exposure. Finally, a meta-analysis was conducted to summarize these findings. The study found positive correlations between SAH and both GBPA-Pyridoxal 5 phosphate biosynthesis I (OR=1.48, 95% CI, 1.04-2.12) and GBPA-glucose biosynthesis I (OR=0.68, 95% CI, 0.52-0.90). Increased levels of urokinase-type plasma activator were also associated with SAH (OR=1.17, 95% CI, 1.04-1.32). Associations were observed with SAH for CD80 on CD62L+ plasmacytoid dendritic cells, CD80 on plasmacytoid dendritic cells, CD123 on CD62L+ plasmacytoid dendritic cells, and SSC-A on plasmacytoid dendritic cells. This study, through Mendelian randomization and meta-analysis, established links between SAH and four inflammatory cells, one inflammatory protein, and two gut microbiota-related pathways. These findings suggest potential treatment targets for SAH, highlighting the importance of modulating gut microbiota and utilizing anti-inflammatory drugs in its management.

Heterozygous loss-of-function mutations in the progranulin gene (GRN) are a major cause of frontotemporal dementia due to progranulin haploinsufficiency; complete deficiency of progranulin causes neuronal ceroid lipofuscinosis. Several progranulin-deficient mouse models have been generated, including both knockout mice and knockin mice harboring a common patient mutation (R493X). However, the Grn^R493X mouse model has not been characterized completely. Additionally, while homozygous Grn^R493X and Grn knockout mice have been extensively studied, data from heterozygous mice is still limited. Here, we performed more in-depth characterization of heterozygous and homozygous Grn^R493X knockin mice, which includes biochemical assessments, behavioral studies, and analysis of fluid biomarkers. In the brains of homozygous Grn^R493X mice, we found increased phosphorylated TDP-43 along with increased expression of lysosomal genes, markers of microgliosis and astrogliosis, pro-inflammatory cytokines, and complement factors. Heterozygous Grn^R493X mice did not have increased TDP-43 phosphorylation but did exhibit limited increases in lysosomal and inflammatory gene expression. Behavioral studies found social and emotional deficits in Grn^R493X mice that mirror those observed in Grn knockout mouse models, as well as impairment in memory and executive function. Overall, the Grn^R493X knockin mouse model closely phenocopies Grn knockout models. Lastly, in contrast to homozygous knockin mice, heterozygous Grn^R493X mice do not have elevated levels of fluid biomarkers previously identified in humans, including neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) in both plasma and CSF. These results may help to inform pre-clinical studies that use this Grn knockin mouse model and other Grn knockout models.