Frontiers in Molecular Neuroscience最新文献

The granin gene family of neuropeptides functions as peptide neurotransmitters in the brain for the regulation of neural functions that regulate behaviors. Granins are involved in regulating cognition, memory, depression, aggression, stress, energy expenditure, inflammation, and related. Development of the human brain involves formation of synapses and their spectrum of neurotransmitters to establish neural connections that are required for brain functions. Therefore, the goal of this study was to analyze the gene expression profiles of the granin neurotransmitter genes during human brain development at prenatal, infancy, childhood, adolescence, and adult stages. Granin gene expression in brain development was assessed by quantitative RNA sequencing data from the Allen Human Brain Atlas resource. VGF (neurosecretory protein VGF) expression was significantly increased during development during the prenatal to childhood through adult stages in the anterior cingulate cortex, dorsolateral prefrontal cortex, inferolateral temporal cortex, orbital frontal cortex, posteroventral parietal cortex, primary somatosensory cortex, and primary visual cortex regions. SCG2 (secretogranin 2) expression was also significantly increased from prenatal to infancy through adult stages in anterior cingulate cortex, dorsolateral prefrontal cortex, inferolateral temporal cortex, orbital frontal cortex, posterior superior temporal cortex, posteroventral parietal cortex, primary somatosensory cortex, and primary visual cortex. A modest number of brain regions showed increased CHGA, CHGB, and SCG3 expression in the postnatal periods compared to the prenatal periods. Further, the SCG5, PCSK1N, and GNAS genes displayed minimal changes throughout development. Overall, these results demonstrate developmental upregulation of VGF and SCG2 genes, with lesser upregulation of CHGA, CHGB, and SCG3 genes, and almost no changes in SCG5, PCSK1N, and GNAS genes during development. These findings illustrate the differential regulation of granin genes during human brain development.

Lipid droplets (LDs), once considered inert lipid stores, are now recognized as active regulators of lipid metabolism, stress responses, and protein quality control in the brain. Their dysregulation is increasingly linked to neurodegenerative diseases, notably Parkinson's disease (PD). This review explores the emerging bidirectional relationship between LDs and α-synuclein (α-Syn), a key pathological hallmark of PD. α-Syn can promote LD accumulation by modulating lipid metabolism and inhibiting lipolysis, while LDs can facilitate α-Syn aggregation through specific lipid-protein and membrane interactions. We summarize current evidence on LD structure, function, and dynamics in neuronal and glial cells, and discuss how alterations in lipid composition, oxidative stress, and associated proteins contribute to PD pathology. Understanding the LD-α-Syn interplay reveals new avenues for therapeutic strategies aimed at restoring lipid homeostasis, enhancing LD turnover, and reducing α-Syn toxicity.

A potential analgesic medicinal substance has been discovered, the ouabain-Ca²⁺ chelate complex (EO). As we have found, the specific EO binding to the Na,K-ATPase (NKA) in nanomolar concentrations triggers several signaling cascades in the nociceptive neuron, two of which have been discussed elsewhere. The docking results indicate that the molecular basis for the specificity of EO-NKA binding is the formation of two intermolecular ionic bonds between the chelated Ca²⁺ cation and two NKA carboxylate anion, Glu116 and Glu117. The third downstream EO-triggered NKA/Src/PKA/p38 MAPK/NF-κB signaling pathway, likely, controls the GAP43 gene expression, which results in this case in the neurite-inhibiting effect at the tissue level. The strong EO analgesic effect at both the spinal and supraspinal levels has been demonstrated in the formalin test. EO is a promising candidate for the role of a novel and safe analgesic, which might be particularly effective for the treatment of the tumor-associated pain syndromes due to its possible cytostatic function.

Ischemic stroke (IS) represents the leading global cause of acquired neurological disability and vascular-related mortality. However, diagnostic challenges persist in cases with atypical presentations. Lactylation modification exerts critical regulatory roles in disease pathogenesis and progression, and thus positioning as a potential diagnostic biomarker. We utilized weighted gene co-expression network analysis (WGCNA), gene ontology (GO)and Kyoto Encyclopedia of Genes and Genomes (KEGG), immune infiltration assessment, consensus clustering (via ConsensusClusterPlus), and multiple machine learning algorithms-including random forest (RF), support vector machine (SVM), neural network (NM), and generalized linear models (GLMs)-along with real-time-quantitative polymerase chain reaction (RT-qPCR) and western blot validation, to analyze gene expression omnibus (GEO) datasets. Our findings indicate that immune infiltration may play an important role in IS, with neutrophils and T cell receptor signaling pathway emerging as the most important immune cells and signaling pathway, respectively. Six hub genes, namely SLC2A3, NDUFB11, GTPBP3, SLC16A3, PUS1, and GRN, were identified and verified through RT-qPCR and the western blot. Surprisingly, the area under the curve (AUC) of the prediction model reached 0.968, with a 95% confidence interval ranging from 0.928 to 1. Extensive validation using multiple external GEO datasets confirmed the accuracy of the prediction model in five independent datasets. Furthermore, we observed that different concentrations of lactate could further suppress the proliferation of nerve cells following oxygen-glucose deprivation/reperfusion (OGD/R). This study provides a new diagnostic strategy for the early diagnosis of IS through the established diagnostic prediction model.

Continuous vision relies on the recycling of visual pigment chromophore, which is photoisomerized during the process of vision. In vertebrates, this recycling is mediated by a complex network of biochemical reactions distributed across different cell types referred to as the visual cycle. In this review, we outline both historical and recent findings on the visual cycle and its connection to outer retinal dystrophies. Particular emphasis is placed on the recycling of cone, rather than rod, visual pigments, and on the utility of the zebrafish (Danio rerio) as a model for such studies.

Introduction: Hypoxia, an inadequate tissue oxygen supply, poses a threat to the brain, which relies heavily on oxygen for its energy requirements. However, mild oxygen deficiency triggers cellular stress, leading to a defensive state known as hypoxic preconditioning (HPC). Despite its potential as a treatment option for neurodegenerative diseases, research on preconditioning remains a challenge. Therefore, this study aimed to further explore biochemical changes induced by HPC, with a specific emphasis on mitochondria, the primary oxygen consumers.

Methods: We assessed the neuroprotective impact of a HPC protocol used by examining the seizure thresholds of mice. Additionally, we analyzed mitochondrial respiration under varying oxygen levels, reactive oxygen species (ROS) production, and mitochondrial morphology following HPC treatment.

Results: HPC treatment of mice raised their seizure threshold, indicating an enhanced resistance to epileptic seizures and highlighting the protective effects of the HPC protocol. HPC increased mitochondrial oxygen consumption and ROS production, primarily originating from Complex I. Importantly, ROS levels remaining within the physiological range potentially activate cell signaling pathways. Our findings underscored the importance of controlling oxygen at physiologically relevant intracellular tissue levels (intracellular tissue normoxia) during mitochondrial respiration measurements. Notably, HPC-treated mitochondria generally exhibited reduced oxygen consumption compared to controls under effectively hyperoxic air-saturated oxygen conditions. However, mitochondrial respiration was increased under intracellular tissue normoxia in comparison to the controls measured at air saturation. Moreover, following HPC treatment, we observed alterations in mRNA expression levels associated not just with mitochondrial dynamics but also with perinuclear mitochondrial accumulation and pro-survival signaling. Furthermore, an immediate increase in mitochondrial fusion was observed following hypoxia treatment.

Background: Transient cerebral ischemia is a strong warning sign of cerebral infarction (CI). Early objective risk assessment in patients with transient cerebral ischemia can effectively help prevent the occurrence of CI.

Objective: The study aimed to explore the predictive value of SNHG1/miR-194-5p in combination with carotid ultrasound for predicting the occurrence of CI in patients with transient cerebral ischemia.

Patients and methods: This study was a prospective observational study. A total of 189 patients with transient cerebral ischemia were included and divided into the CI group (n = 67) and the non-CI group (n = 122) based on whether CI occurred within 90 days. The clinical data and laboratory indexes of the two groups were compared. RT-qPCR was employed to examine the levels of SNHG1/miR-194-5p. Logistic regression analysis and receiver operating characteristic (ROC) curve analysis were performed based on serum SNHG1/ miR-194-5p levels and the degree of carotid artery stenosis. In addition, bioinformatics analysis was carried out to identify the target genes of miR-194-5p.

Results: The results showed that, compared to the non-CI group, the expression of SNHG1 in the serum of the CI group was upregulated, while the expression of miR-194-5p was downregulated. Logistic regression analysis showed that the expression of miR-194-5p (OR = 0.067, p < 0.001) and SNHG1 (OR = 25.984, p < 0.001) and the degree of carotid artery stenosis (OR = 1.152, p = 0.001) were significantly correlated with CI. The combined detection of these three indicators yielded an AUC value of 0.953 for predicting CI. Its sensitivity was 89.55% and specificity was 86.89%, indicating higher diagnostic efficiency than any single indicator. Furthermore, bioinformatics analysis revealed that the target gene of miR-194-5p was enriched in various disease pathways, especially those related to neurodegeneration, providing a new direction for exploring the mechanism of CI.

Conclusion: Serum SNHG1/miR-194-5p levels combined with carotid ultrasound show high predictive accuracy for the short-term occurrence of CI in patients with transient cerebral ischemia.

The G4C2 repeat expansion in C9orf72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). While healthy individuals have fewer than 30 repeats, affected patients may carry hundreds to thousands. This expansion accounts for approximately 40% of familial ALS and 25% of familial FTD cases, and between 5 and 10% cases of sporadic ALS and FTD. Three overlapping pathological mechanisms have been proposed for the C9orf72 expansion: loss of function due to protein deficiency, gain of function through RNA foci, and the production of toxic dipeptide repeat proteins (DPRs) via repeat-associated non-ATG (RAN) translation. This systematic review investigates the role of DNA damage in C9orf72-related ALS-FTD. Analysis of twelve peer-reviewed studies showed that C9orf72 repeat expansions and DPRs compromise genome stability across four experimental models: human cell lines, induced pluripotent stem cell-derived neurons, rodent neurons, and postmortem tissue. We identified four mechanisms underlying DNA damage accumulation: disruption of the ATM pathway, impairment of DNA repair efficiency, formation of R-loops, and mitochondrial dysfunction with oxidative stress. In addition, several consequences of DNA damage were identified, including misrepair-mediated repeat expansion and activation of STING pathway. These findings highlight the key role of DNA damage in C9orf72-related pathology. Consistent with this, targeting DNA damage response factors extended lifespan and improved motor function in mouse models. This review highlights the contribution of DNA damage to C9orf72 pathology and suggest new therapeutic avenues, including personalized approaches based on genetic background.

Alpha-neurexins (α-Nrxns) are synaptic adhesion molecules that play crucial roles in synapse organization, specificity, and function. This review provides a comprehensive overview of α-Nrxns, covering their gene organization, molecular architecture, and roles in both physiological and pathological contexts. We begin by detailing the unique structural properties of α-Nrxns, particularly their large extracellular regions and complex alternative splicing, which facilitate diverse trans-synaptic interactions. We then examine their critical roles in regulating presynaptic neurotransmitter release, postsynaptic receptor function, and overall synaptic organization. While deletion of α-Nrxns in mice results in only modest morphological brain abnormalities, it causes profound deficits in synaptic function, underscoring their role in fine-tuning neural circuit activity in a context-dependent manner. We also explore how specific α-Nrxn ligands such as neurexophilins or IgSF21 contribute to synaptic diversity. Furthermore, we discuss emerging evidence linking α-NRXNs to various neurodevelopmental and psychiatric disorders, including autism spectrum disorder, schizophrenia, and intellectual disability. These links are supported by both genetic association studies and behavioral analyses in α-Nrxn mutant mice, which exhibit phenotypes that partially mirror symptoms observed in human disorders. Finally, we highlight recent advances in human induced pluripotent stem cell (hiPSC)-derived neuronal models, which offer powerful platforms to investigate α-NRXN-associated disease mechanisms at the cellular level. These models enable the study of patient-specific neurobiological alterations and support the development of targeted therapeutic strategies. Collectively, this review emphasizes the pivotal role of α-Nrxns in maintaining synaptic integrity and demonstrates how their dysfunction contributes to a broad spectrum of brain disorders, providing valuable insights for future translational research.