Journal of Molecular Neuroscience最新文献

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder with an increasing prevalence worldwide, including in Saudi Arabia. Emerging evidence suggests that biochemical markers, such as oxidative stress indicators, neurotransmitter levels, and lipid profiles, play a significant role in ASD’s pathology and may also elevate cardiovascular and metabolic risks in affected individuals. This systematic review and meta-analysis synthesize current findings on these biomarkers, with a particular focus on the Saudi population, to elucidate their relationship with ASD pathology and associated health outcomes. Following the PRISMA guidelines, data from 41 studies on oxidative stress markers, neurotransmitters, lipid profiles, and immune markers were analyzed. Searches were conducted across major databases, including PubMed, Scopus, Web of Science, and Embase, and effect sizes were calculated using standardized mean differences with a 95% confidence interval. To further interpret the data, bioinformatics tools such as Reactome, Panther, and STRING were employed to analyze biomarker pathways. The results highlight a significant association between elevated oxidative stress and mitochondrial dysfunction in individuals with ASD, with profound effects on gastrointestinal and mitochondrial health. These biochemical abnormalities disrupt synaptic plasticity and drive chronic neuroinflammation, which impairs neurodevelopmental processes, contributing to the pathology of ASD. The meta-analysis reveals minimal heterogeneity (I² = 0.02%) and limited publication bias, supporting the reliability of these associations. The findings underscore the need for a multidisciplinary approach to ASD management in Saudi Arabia, emphasizing biomarker-based diagnostics and personalized treatment strategies. Future research directions include developing individualized diagnostic and therapeutic frameworks utilizing these biomarkers to enhance ASD-related health outcomes.

Impairment in mitochondrial function and ubiquitin–proteasome system (UPS) and alpha-synuclein (α-Syn) aggregation are implicated in Zn-induced neurotoxicity. A link among these events leading to Zn-induced neurotoxicity is not yet properly deciphered. Therefore, the study intended to check the existence of a crosstalk between the mitochondria and UPS and its further link to α-Syn aggregation. The study also aimed to investigate the efficacy of tempol, a SOD mimetic and silymarin, a natural antioxidant, against Zn-induced alterations in animals and differentiated cells. Zn reduced the locomotor activity, dopamine content and tyrosine hydroxylase (TH) expression in the exposed animals. Zn augmented the levels of mitochondrial reactive oxygen species, α-Syn and protein-ubiquitin conjugates. Mitochondrial membrane potential, adenosine triphosphate (ATP) production, UPS-associated enzymatic activities and levels of UPS subunits (SUG-1 and β-5) were attenuated in Zn-exposed animals. While Zn augmented the expression of heat shock protein 110 (HSP110), peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1α) and Parkin translocation, the mitochondrial PTEN-induced kinase-1 (PINK-1) level was attenuated. In addition to tempol and silymarin, a mitochondrial permeability transition pore inhibitor, cyclosporine A, also alleviated the Zn-induced changes in animals. Similar trends in a few parameters were also observed in the differentiated human neuroblastoma SH-SY-5Y cells. Besides, UPS inhibitor, MG132, enhanced Zn-induced UPS impairment, protein aggregation and mitochondrial dysfunction in differentiated cells. These results suggest that mitochondrial dysfunction triggers UPS impairment or vice versa that elevates α-Syn aggregation and consequent neuronal death. Furthermore, tempol and silymarin ameliorate the mitochondrial and UPS impairments and α-Syn aggregation thereby providing protection from Zn-induced neurotoxicity.

Ischemic stroke is a leading cause of disability and death worldwide, largely due to its increasing incidence associated with an aging population. This condition results from arterial obstruction, significantly affecting patients' quality of life and imposing a substantial economic burden on healthcare systems. While current treatments primarily focus on the rapid restoration of blood flow through thrombolytic therapy or surgical interventions, a limited understanding of neuronal injury mechanisms hampers the development of more effective treatments.This article explores the interplay among various cell death pathways—necroptosis, apoptosis, autophagy, ferroptosis, and pyroptosis—in the context of ischemic stroke to identify novel therapeutic targets. Each mode of cell death displays unique characteristics and roles post-stroke, and the activation of these pathways may vary across different animal models, complicating the translation of therapeutic strategies to clinical settings. Notably, the interaction between apoptosis and necroptosis is highlighted; inhibiting apoptosis might heighten the risk of necroptosis. Therefore, a balanced regulation of these pathways could promote enhanced neuronal survival.Additionally, we introduce PANoptosis, a form of cell death that encompasses pyroptosis, apoptosis, and necroptosis, emphasizing the complexity and potential therapeutic implications of these interactions. In summary, understanding the relationships among these cell death mechanisms in ischemic stroke is vital for developing new neuroprotective agents. Future research should aim for combinatorial interventions targeting multiple pathways to optimize treatment strategies and improve patient outcomes.

The objective of this study is to explore the association of common genetic variation of anxiety disorders and essential tremor (ET). We genotyped 25 anxiety-specific risk variants in a cohort of 478 unrelated ET patients and 504 age and gender-matched healthy controls from eastern China using a MassARRAY system. The association between candidate variants and ET patients was evaluated using gene-based analysis. A total of 159 patients (33.3%) had anxiety. In genotypic analysis, rs708012 (in an intergenic region) in the dominant models was found to be significantly associated with ET (P < 0.001, OR = 0.605). In allelic analysis, the carriers of the C allele of NTRK2 rs1187280 (P = 0.027, OR = 0.626), T allele of TMEM106B rs3807866 (P = 0.030, OR = 1.287), and T allele of rs708012 (P < 0.001, OR = 0.679) occupy a larger proportion of ET patients compared with healthy controls. Anxiety-specific risk SNPs of TMEM106B rs3807866 increase the risk for ET, while two SNPs of NTRK2 rs1187280 and rs708012 show a protective role.

Ischemic stroke leads to permanent damage to the affected brain tissue, with strict time constraints for effective treatment. Predictive biomarkers demonstrate great potential in the clinical diagnosis of ischemic stroke, significantly enhancing the accuracy of early identification, thereby enabling clinicians to intervene promptly and reduce patient disability and mortality rates. Furthermore, the application of predictive biomarkers facilitates the development of personalized treatment plans tailored to the specific conditions of individual patients, optimizing treatment outcomes and improving prognoses. Bioinformatics technologies based on high-throughput data provide a crucial foundation for comprehensively understanding the biological characteristics of ischemic stroke and discovering effective predictive targets. In this study, we evaluated gene expression data from ischemic stroke patients retrieved from the Gene Expression Omnibus (GEO) database, conducting differential expression analysis and functional analysis. Through weighted gene co-expression network analysis (WGCNA), we characterized gene modules associated with ischemic stroke. To screen candidate core genes, three machine learning algorithms were applied, including Least Absolute Shrinkage and Selection Operator (LASSO), random forest (RF), and support vector machine-recursive feature elimination (SVM-RFE), ultimately identifying five candidate core genes: MBOAT2, CKAP4, FAF1, CLEC4D, and VIM. Subsequent validation was performed using an external dataset. Additionally, the immune infiltration landscape of ischemic stroke was mapped using the CIBERSORT method, investigating the relationship between candidate core genes and immune cells in the pathogenesis of ischemic stroke, as well as the key pathways associated with the core genes. Finally, the key gene VIM was further identified and preliminarily validated through four machine learning algorithms, including generalized linear model (GLM), Extreme Gradient Boosting (XGBoost), RF, and SVM-RFE. This study contributes to advancing our understanding of biomarkers for ischemic stroke and provides a reference for the prediction and diagnosis of ischemic stroke.

Cerebral ischemia–reperfusion injury (CIRI), which stays unresolved in the clinic, occurs after recanalization of blood vessels serving brain tissues in acute ischemic stroke patients and can result in massive brain cell death, and cell ferroptosis contributes greatly to this process. Our research firstly found that TNFSF9 expression harbored diagnostic value on CIRI patients and intended to further investigate its regulatory mechanism in CIRI, which might facilitate its diagnostic and therapeutic application in the clinic. The level of TNSF9 mRNA was augmented in the plasma of CIR patients, and its silence impeded ferroptosis, apoptosis, and release of inflammatory mediators of BMECs with OGD/R treatment. Besides, SP1 positively regulated TNFSF9 expression as one of its transcription factors, and TNFSF9 overexpression reversed SP1 silence-mediated inhibition on ferroptosis, apoptosis, and release of inflammatory mediators in OGD/R-treated BMECs. In addition, silencing SLC3A2 could neutralize the benefit effects of TNFSF9 downregulation on BMECs under OGD/R context in vitro, and silencing TNFSF9 neutralized necrotic volumes in rat brain induced by CIRI via modulating SLC3A2 expression in vivo. TNFSF9 regulated by SP1 aggravated CIRI via boosting ferroptosis, apoptosis, and release of inflammatory mediators of BMECs under OGD/R situation by suppressing SLC3A2 expression in vitro and in vivo.

CSF1R-related leukoencephalopathy (CSF1R-L) and AARS2-related leukoencephalopathy (AARS2-L) were two disease entities sharing similar phenotype and even pathological changes. Although clinically, radiologically, and pathologically similar, they were caused by mutation of two different genes. As the rarity of the two diseases, the differential diagnosis of them was difficult. 23 CSF1R-L and 6 AARS2-L patients were enrolled from the Leukoencephalopathy Clinic, Peking Union Medical College Hospital in China. Detailed clinical information, neuroimaging manifestations, and genetic data were collected and analyzed. Demographically, female patients were more in AARS2-L than CSF1R-L. Clinically, cognitive impairment and emotion/personality change were common in both groups. Bulbar palsy, extrapyramidal symptoms, and hemiplegia/pyramidal impairment were more common in CSF1R-L, while ataxia was significantly more common in AARS2-L. Abnormal menstruation including infertility was significantly more in AARS2-L. Radiologically, similar features were found, including lateral ventricle-centered white matter lesions, involving corpus callosum, avoiding U fibers. The lesions showed persistent hyperintensity on DWI image and were not contrasted after gadolinium enhancement. In CSF1R-L, the lesions could be widespread confluent or patchy and spotted, extending to centrum semiovale and subcortical white matter occasionally, which was significantly different from AARS2-L. Besides, brain stem lesion caused by pyramidal degeneration, spotted or linear calcification and obviously brain atrophy were common in CSF1R-L. In AARS2-L, periventricular white matter rarefaction was significantly common. No genotype and phenotype association was found in these two diseases. Although similar, there were several clinical and radiological features helping differentiating the two distinct diseases.

Glioma is a highly aggressive and invasive brain tumor with limited treatment options, highlighting the need for novel therapeutic approaches. Kinesin superfamily proteins (KIFs) are a diverse group of motor proteins that play essential roles in cellular processes such as mitosis, intracellular transport, and signal transduction, all of which are crucial for tumorigenesis. This review focuses on the multifaceted role of KIFs in glioma, examining their clinical relevance, contribution to tumor progression, and potential as therapeutic targets. We discuss how KIFs influence key aspects of glioma biology, including cell proliferation, invasion, migration, and metastasis. Furthermore, we explore the regulation of the cell cycle and critical signaling pathways associated with glioma, such as PI3K-Akt, Wnt/β-catenin, and Hedgehog signaling by KIFs. The review also addresses the emerging interplay between KIFs and non-coding RNAs, including circular RNAs (circRNAs) and microRNAs (miRNAs), in glioma progression. Finally, we examine current therapeutic strategies targeting KIFs, including immunotherapy, chemotherapy, and small-molecule inhibitors, and their potential to improve treatment outcomes for glioma patients. By synthesizing these insights, this review underscores the significance of KIFs in glioma pathogenesis and their promise as novel therapeutic targets in the fight against glioma.

Primary brain tumors that were the most severe and aggressive were called glioblastoma multiforme (GBM). Cancers are caused in part by aberrant expression of circular RNA. Often referred to as competitive endogenous RNA (ceRNA), circRNA molecules act as “miRNA sponges” in cells by decreasing the inhibitory impact of miRNA on their target genes and hence raising the expression levels of those genes. circRNA molecules are rich in miRNA binding sites. The discovery of more structurally diverse and GBM-related circRNAs has great promise for the use of GMB prognostic biomarkers and therapeutic targets, as well as for comprehending the molecular regulatory mechanisms of GBM. In this work, we present an overview of the circRNA expression patterns associated with GBM and offer a potential integrated electrochemical strategy for detecting circRNA with extreme sensitivity in the diagnosis of glioblastoma.

Graphical Abstract

The circular RNA (circRNA) regulates both physiological and pathological processes in glioblastoma multiforme disease. Hence, it could serve as a biomarker as well as a therapeutic target.

The purpose of this study was to investigate the expression of miR-499a-5p in children with autism spectrum disorders (ASD) and its value in early diagnosis of ASD. This is a retrospective case–control study that included 40 children with ASD as a case group and 43 healthy children as a control group. Magnetic resonance imaging (MRI) was performed on all subjects, and the children were scored with childhood autism rating scale (CARS) and autism behavior checklist (ABC). The expression of miR-499a-5p in serum was detected by RT-qPCR, and the diagnostic value of miR-499a-5p in ASD was evaluated by ROC curve. Pearson correlation coefficient was used to evaluate the correlation between miR-499a-5p levels and scores. Compared with healthy children, the expression level of serum miR-499a-5p was significantly reduced in children with ASD. ROC curve showed that miR-499a-5p is of high diagnostic value for ASD. The results of MRI suggested that the volume of the amygdala in ASD children was significantly larger than that in healthy children, while the volume of the caudate nucleus was significantly reduced. Correlation results showed that the scores of CARS and ABC in the ASD group were significantly negatively correlated with the levels of miR-499a-5p. In the ASD group, the volume of the amygdala was negatively correlated with the level of miR-499a-5p, while the volume of the caudate nucleus was positively correlated with the level of miR-499a-5p. The decreased expression of miR-499a-5p in the serum of children with ASD was significantly related to the changes in brain volume of children with ASD, and the miRNA showed good diagnostic accuracy in children with ASD.