Journal of Molecular Neuroscience最新文献

The aim of this study was to explore the function of receptor-interacting protein kinase 3 (RIPK3) on retinal neuron damage induced by retinal ischemia/reperfusion (IR). Microglia-specific RIPK3 knockout (KO) mice were employed to establish retinal IR models. Retinal structural and functional status was assessed using hematoxylin and eosin staining along with electroretinogram. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining was employed to detect the situations of apoptotic cell death. Immunofluorescence and western blot were applied to detect the proteins associated with necroptosis and retinal inner neurons. Following retinal IR, necroptosis-related protein RIPK3 became activated within microglia, inducing the activation of mixed lineage kinase domain-like protein (MLKL). RIPK3 KO significantly alleviated IR-induced retinal morphological defects and protected against IR-induced visual dysfunction by preserving neurons within the retina. Additionally, the counts of TUNEL⁺ apoptotic cells were markedly reduced within RIPK3 KO mice after IR, along with a decrease in retinal inflammatory responses. Mechanistically, IR injury promoted retinal ganglion cells (RGCs) death by activating RIPK3 to induce MLKL and fibroblast growth factor 2 (FGF2) activation; however, RIPK3 KO suppressed this process. After IR, RIPK3-mediated necroptosis in microglia induced its activation, promoting inflammatory responses and thereby facilitating RGCs death. Targeting RIPK3 could protect retinal neurons from injury after IR through suppressing the MLKL/FGF2 pathway, rendering this a potential curative measure for RGCs degeneration in ischemic retinopathy.

Pathogenic variants in EPG5 have been associated with Vici syndrome (OMIM #242840) characterized by agenesis of the corpus callosum (ACC), cataracts, cardiomyopathy, hypopigmentation, and immunodeficiency as hallmark features. Additional variable features include microcephaly, hypotonia, developmental delay, and growth retardation. Recently, few reports described milder cases with a neurodevelopmental phenotype and less systemic involvement harboring EPG5 variants suggesting a broader clinical spectrum. Herein, we describe seven patients from six unrelated Egyptian families in whom exome sequencing identified six homozygous (five novel and one previously reported) EPG5 variants. Patients presented with global developmental delay, microcephaly, hypotonia, dystonia, and failure to thrive. Seizures were evident in two patients and showed a variable response to antiepileptic drugs. Fair color of hair and skin was noted in four out of seven patients (57%), while cataracts and cardiomyopathy were observed in one patient each (14%). In addition to ACC, cerebellar and pontine hypoplasia, delayed myelination, and ventricular dilatation were evident in all patients. Interestingly, deep fissure in the frontal lobes, extending from the frontal horn to the frontal pole, was documented in six patients and appears to represent a characteristic feature associated with EPG5 variants. Our study highlights the phenotypic variability associated with EPG5 variants and emphasizes the presence of a phenotypic spectrum ranging from the classic severe Vici syndrome to a neurodevelopmental disorder with less systemic manifestations and a longer survival rate.

Attention deficit hyperactivity disorder (ADHD) is a disorder characterized by symptoms of inattention, impulsivity, and hyperactivity, which can significantly impair individuals’ quality of life and lead to various challenges in their social interactions, relationships, professional endeavors, and academic pursuits. This disorder can manifest in both children and adults, and it has been established that genetic and environmental factors contribute to its etiology. Existing data indicate that individuals with ADHD are at a higher risk of substance use, and some may develop cannabis dependence or engage in self-medication with it. It has been hypothesized that individuals with ADHD may utilize cannabis to mitigate certain symptoms, such as anxiety, or to alleviate the adverse effects of their prescribed medication. Furthermore, both in vivo and clinical investigations have reported that cannabinoids, including cannabidiol, may possess potential therapeutic effects in ADHD patients or animal models. This study aims to provide a comprehensive review of the current literature on the impact of cannabinoids on ADHD and to elucidate the possible pharmacological mechanisms through which cannabinoids might exert their therapeutic outcomes.

Neurological disorders such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), Schizophrenia (SCZ), and epilepsy pose a significant global health challenge, particularly among the ageing population. With Alzheimer’s cases projected to double in the next 30 years, the lack of effective treatments presents a critical concern, leading to substantial social and economic burdens. While rodent models have been instrumental in elucidating disease mechanisms and identifying therapeutic targets, their limited translational success necessitates exploring alternative model systems. This review highlights the increasing integration of non-rodent models, including invertebrates (Drosophila melanogaster and Caenorhabditis elegans), lower vertebrates (Danio rerio), and higher-order mammals (non-human primates), alongside emerging approaches such as Octopus models, 2D and 3D cell culture systems, computational models, and in silico methodologies. These alternative models provide unique advantages in studying neural development, function, and pathology, offering improved translational relevance. By leveraging the complementary strengths of these systems, researchers can refine therapeutic strategies and advance our understanding of complex neurological disorders.

Graphical Abstract

Postoperative cognitive dysfunction (POCD) has a significant impact on the postoperative life ability of the elderly, and nearly 50% of the elderly are at risk globally, but the molecular mechanism of its pathogenesis is still unclear. The aim of this study was to discuss the expression of lncRNA MYL2 in older rats and its effects to provide possible targets for future treatment. A POCD model of aged rats was established by osteotomy and sevoflurane, cognitive function was measured by the water maze (MWM), and the concentrations of tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-1β, and oxidative stress–related factors in the hippocampal tissue of rats were detected by enzyme-linked immunosorbent assay. Luciferase reporter gene analysis was used to detect the target gene of the targeting relationship between MYL2 and miR-661. Cell viability and apoptosis rate were assessed using CCK-8 and flow cytometry. MYL2 was up-regulated by Sev treatment in the rat hippocampus. Overexpression of MYL2 prolonged the escape latency of rats, shortened the time spent in the target quadrant of rats, and reduced the number of platform crossings. At the same time, the concentrations of pro-inflammatory factors and markers of oxidative stress were increased. miR-661 is a miRNA targeting MYL2. miR-661 could reverse the exacerbation effect of MYL2 on POCD. MYL2 serves as a potential sponge of miR-661, and its up-regulation is linked to exacerbated neuroinflammation, oxidative damage, and cellular dysfunction in POCD.

Alzheimer's disease (AD) is the leading cause of dementia, characterized by cognitive decline and neurodegeneration. Given the limitations of current treatments, research has turned to natural substances such as piperine, which is known for its neuroprotective properties. This study investigates the effects of piperine on cognitive function and genes associated with oxidative stress, inflammation, and necroptosis-related genes in a rat model of cognitive impairment. Fifty adult male Wistar rats were used, divided into five groups: an intact group, a control group (vehicle solution followed by scopolamine), and three experimental groups receiving piperine (5, 10, and 20 mg/kg) followed by scopolamine during the training period. Behavioral assessment was conducted using the Morris Water Maze (MWM) test. Hippocampal tissue was collected after euthanasia for gene expression analysis of Nrf2, HO‑1, TNF‑α, Fas, TRAIL, MLKL, and Caspase‑8. Spatial learning and memory improved significantly in piperine-treated groups, with no impact on swimming velocity, indicating cognitive enhancement without affecting motor functions in the scopolamine-induced cognitive impairment model. Piperine pretreatment prevented oxidative stress and inflammation, as evidenced by the restoration of Nrf2, HO-1, and Caspase-8 and the reduction of TNF-α, Fas, TRAIL, and MLKL expression levels. These findings suggest that piperine has antioxidative, anti‑inflammatory, and cognitive‑enhancing effects, with particular effects possibly on necroptosis, and could be a valuable addition to the current AD treatment paradigm, warranting further investigation in clinical trials.

This work examined the causal link between palmitoylation-related genes and Parkinson’s disease (PD) by Mendelian randomization (MR). We conducted two-sample Mendelian randomization utilizing genome-wide association study (GWAS) summary statistics. Expression quantitative trait loci (eQTL) data for palmitoylation genes were sourced from eQTLGen, whilst PD data were derived from the GWAS Catalogue (15,056 cases, 12,637 controls) and FinnGen (4,681 cases, 407,500 controls). Instrumental variables (p < 5 × 10⁻⁶, r² < 0.1) were examined using inverse-variance weighted (IVW) regression, along with weighted median, MR-Egger, and Summary-data-based MR (SMR) methods. Sensitivity analyses evaluated pleiotropy and resilience. The IVW analysis revealed significant correlations with Parkinson’s disease for ZDHHC14 (OR = 1.09, P = 0.037), ZDHHC17 (OR = 1.18, P = 0.002), ZDHHC2 (OR = 1.16, P = 0.039), ZDHHC20 (OR = 0.82, P = 0.019), and ZDHHC8 (OR = 1.24, P = 0.022). SMR validation corroborated solely ZDHHC8 (OR = 1.35, P = 0.040). Replication in FinnGen corroborated ZDHHC1, ZDHHC13, ZDHHC17, and ZDHHC8. No heterogeneity or pleiotropy was observed (P > 0.05). ZDHHC8 has a strong causative relationship with PD, suggesting that palmitoylation dysregulation plays a role in disease etiology. These findings underscore synaptic dysfunction as a viable therapeutic target.

By analyzing genetic polymorphisms in the genes of patients and control subjects, it is possible to find the correlation of these factors with the phenotypic variation as mental disorders to propose hypotheses about the possible mechanisms of specific diseases. Accordingly, in the present study, the role of oxytocin receptor and dopamine D2 receptor polymorphisms in the personality traits of optimistic, pessimistic and intermediate individuals was investigated. In this study, the polymorphism of DRD2 receptors and oxytocin receptor genes in saliva samples of Iranian volunteers was investigated. Accordingly, saliva samples were prepared from 90 individuals. The mental status of these individuals (optimistic, pessimistic and intermediate) was determined by a specialist physician. Then, the DNA of the sample was extracted and the presence or absence of the rs53576 polymorphism in the OXTR gene and the rs1800497 polymorphism in the DRD2 gene was examined using PCR reaction and sequencing. The results showed a significant association between the frequency of the rs53576 polymorphism in the OXTR gene and pessimism. In fact, the A allele in this polymorphism caused a 2.4-fold increase in pessimism in the studied individuals. However, no significant association was observed between the rs1800497 polymorphism and the traits of optimism and pessimism. Such studies require more detailed assessments such as brain scans, but due to the high cost of such tests, genetic studies can be used as the first step to confirm or reject the association of the polymorphism with the aforementioned trait.

This work sought to examine the causal link between palmoyl-protein-modifying genes (ZDHHC family) and epilepsy by Mendelian randomisation (MR), utilising multi-level genomic data. A two-sample MR analysis was performed utilising publicly accessible blood and brain tissue expression quantitative trait locus (eQTL) data as exposure variables and epilepsy genome-wide association study (GWAS) data from the FinnGen as the outcome measure. The major analysis method utilised was inverse variance weighting (IVW), with robustness validation conducted by weighted median and MR-Egger procedures. Subsequently, summary-data-based MR (SMR) analysis confirmed signal colocalization, supplemented by single-cell transcriptomic data (GSE302285) to investigate target gene expression patterns at a cellular granularity. MR analysis indicated that heightened expression of ZDHHC3 (OR = 0.69, 95% CI: 0.57–0.84, p = 0.0002) and ZDHHC20 (OR = 0.88, 95% CI: 0.82–0.94, p = 0.0002) was significantly linked to a decreased risk of epilepsy, while increased expression of ZDHHC8 and ZDHHC18 was associated with an elevated risk. SMR analysis further corroborated the protective roles of ZDHHC3 and ZDHHC20. Layered MR analysis showed that the results are more significant in focal epilepsy. An eQTL study specific to brain cells revealed cell-type specificity in these correlations, with ZDHHC20 demonstrating the most significant protective impact in excitatory neurones (OR = 0.89, p = 0.0273). Single-cell transcriptomics demonstrated that ZDHHC20 was significantly expressed in astrocytes and neurones in the brain tissue of epilepsy patients, while ZDHHC3 was primarily concentrated in neurones. This work genetically confirms that certain palmitoylation genes, notably ZDHHC3 and ZDHHC20, may have causative protective effects against the risk of focal epilepsy, highlighting cell-type-specific processes. This establishes innovative theoretical frameworks for exploring the pathophysiology of epilepsy and formulating targeted treatments.

Emerging data highlight oligodendrocyte dysfunction and myelin degeneration as early contributors to the pathology of Alzheimer’s disease (AD), questioning the conventional neuron-focused amyloid-tau model. This comprehensive review recapitulates both clinical and preclinical data linking oligodendrocytes (OLs) and oligodendrocyte precursor cells (OPCs) to amyloid-β secretion, accelerated cellular ageing, and loss of metabolic and trophic support. Simultaneously, microglial activation and neuroinflammation exacerbate damage to myelin and impair remyelination. High-field imaging technologies are associated with white matter pathology that is evident decades before the onset of cortical atrophy, highlighting the pathogenic importance of glial pathology. We discuss pharmacological strategies to correct OL dysfunction by drug repurposing: first-generation H₁-antihistamine clemastine, which induces OPC maturation by M₁ muscarinic antagonism and ERK/mTOR signalling; H₃-receptor antagonists/inverse agonists (e.g. pitolisant) increase neurotransmitter release and induce CREB-mediated remyelination; and serotonergic GPCR agonists (5-HT₄, 5-HT₆, 5-HT_2C) shift APP processing toward non-amyloidogenic pathways, enhance synaptic proteostasis, and protect OLs against 5-HT toxicity. We provide mechanistic details, comparative profiles, and translational considerations, including blood–brain barrier penetration, pharmacokinetics, and safety considerations, as well as patient stratification. We also cover preclinical models and early clinical trials that demonstrate cognitive benefits and advantages in myelin repair. The limitations of monotherapies imply the promise of combinatorial regimens that attack both histaminergic and serotonergic systems. We present a clinical translation roadmap featuring adaptive, biomarker-responsive trials that utilise enhanced myelin imaging; personalised and multi-omics approaches to medicine; and transdisciplinary collaboration among neuroscience, pharmacology, regulatory bodies, and patient–caregiver groups. The translation of repurposed glial-targeting therapies to clinical practice will require adaptive, biomarker-guided trials, advanced myelin imaging, and intersectoral coordination among neuroscience, pharmacology, and regulatory partners, including engagement with patients and caregivers, as well as ethical input.