Search Results (33)

Synaptic plasticity is the key mechanism underlying learning and memory. Neurexins are pre-synaptic molecules that play a pivotal role in synaptic plasticity, interacting with many different post-synaptic molecules in the formation of neural circuits. Neurexins are alternatively spliced at different splice sites, yielding thousands of isoforms with different properties of interaction with post-synaptic molecules for a quick adaptation to internal and external inputs. The endocannabinoid system also plays a central role in synaptic plasticity, regulating key retrograde signaling at both excitatory and inhibitory synapses. This study aims at elucidating the crosstalk between alternative splicing of neurexin and the endocannabinoid system in the hippocampus. By employing an ex vivo hippocampal system, we found that pharmacological activation of cannabinoid receptor 1 (CB1) with the specific agonist ACEA led to reduced neurotransmission, associated with increased expression of the Nrxn1–3 spliced isoforms excluding the exon at splice site 4 (SS4−). In contrast, treatment with the CB1 antagonist AM251 increased glutamatergic activity and promoted the expression of the Nrxn variants including the exon (SS4+) Knockout of the involved splicing factor SLM2 determined the suppression of the exon splicing at SS4 and the expression only of the SS4+ variants of Nrxns1–3 transcripts. Interestingly, in SLM2 ko hippocampus, modulation of neurotransmission by AM251 or ACEA was abolished. These findings suggest a direct crosstalk between CB1-dependent signaling, neurotransmission and expression of specific Nrxns splice variants in the hippocampus. We propose that the fine-tuned regulation of Nrxn1–3 genes alternative splicing may play an important role in the feedback control of neurotransmission by the endocannabinoid system. Full article

This study aims to identify genetically influenced metabolites (GIMs) associated with SSBP and elucidate their regulatory pathways through metabolome genome-wide association studies (mGWASs). Untargeted metabolomics and genome-wide genotyping were performed on 54 participants from the Systematic Epidemiological Study of Salt Sensitivity (EpiSS). The mGWAS was conducted on 970 plasma metabolites, and their potential biological mechanisms were explored. The multivariable logistic regression model and mendelian randomization (MR) were employed to investigate the association and causal relationship between GIMs and SSBP. Metabolomic analysis was performed on 100 subjects in the replication analysis to validate the GIMs identified in the discovery set and their causal association with SSBP. The mGWAS revealed associations between 1485 loci and 18 metabolites. After performing linkage disequilibrium analysis, 368 independent mQTLs were identified and annotated to 141 genes. These functional genes were primarily implicated in the signal transduction of sinoatrial node and atrial cardiac muscle cells. Five key genes were identified using CytoHubba, including CAMK2A, TIAM1, RYR2, RBFOX1, and NRXN3. One-sample MR analysis revealed 14 GIMs with causal associations to SSBP, with LysoPC (0:0/22:5n-3) positively associated with SSBP (p < 0.05). The causal relationship between Phe-lle and SSBP was validated in the replication analysis. This study elucidates the genetic regulatory mechanisms underlying metabolites and identifies GIMs that are causally associated with SSBP. These findings provide insights into identifying metabolic biomarkers of SSBP and characterizing its genetic and metabolic regulation mechanisms. Full article

Background: The reproductive performance of water buffalo significantly impacts the economic aspects of production. Traditional breeding methods are constrained by low heritability and numerous influencing factors, making it difficult to effectively improve reproductive efficiency. Genome-wide association studies (GWAS) offer new possibilities for exploring reproductive traits in water buffalo, opening up new avenues for efficient breeding. Methods: Using whole-genome resequencing, we identified quantitative trait loci (QTLs) associated with four suggestive reproductive traits: calving interval (CI), calf birth weight (CBW), dam birth weight (BW), and age at first calving (FCA). The study focused on identifying genetic variants that influence these reproductive traits. Results: Our research identified 52 suggestive regulatory loci associated with reproductive traits in water buffalo. Based on a 50 kb interval, we annotated these loci to 58 candidate genes. These loci involve genes such as AGBL4, GRM1, NCKAP5, and NRXN1, which are primarily enriched in pathways including the FOXO signaling pathway, calcium ion pathways, estrogen signaling pathway, and phospholipase D signaling pathway. These pathways directly or indirectly regulate the reproductive efficiency of water buffalo. Conclusions: This study has revealed suggestive regulatory genes (AGBL4, GRM1, NCKAP5, NRXN1) associated with reproductive traits in water buffalo. This not only enhances our understanding of the molecular mechanisms underlying complex traits but also points towards strategies for improving the reproductive capacity of water buffalo. These findings provide a solid foundation for future breeding programs aimed at enhancing water buffalo productivity. Full article

The role of biomarkers in cancer treatment varies significantly depending on the cancer stage. Thus, in clinical practice, tailoring biomarkers to meet the specific needs and challenges of each cancer stage can increase the precision of treatment. Because they reflect underlying genetic alterations that influence cancer progression, copy number variation (CNV) biomarkers can play crucial prognostic roles. In our previous study, we identified potential survival-related genes for colorectal cancer (CRC) by analyzing CNV and gene expression data using a machine-learning approach. To further investigate the biological function of NRXN1, we assessed the use of RNA sequencing, phosphokinase assays, real-time quantitative PCR, and Western blot analysis. We found that NRXN1 copy number deletion was significantly associated with poor overall survival (OS) and recurrence-free survival (RFS), even in patients who received adjuvant chemotherapy. Compared with its expression in normal tissues, NRXN1 expression was lower in tumors, suggesting its potential role as a tumor suppressor. NRXN1 knockdown enhanced CRC cell viability and invasion, and transcriptome analysis indicated that the increased invasion was caused by GSK3β-mediated epithelial–mesenchymal transition. These findings highlight NRXN1 copy number deletion as a novel biomarker for predicting recurrence and survival in patients with resected colon cancer. Full article

Sensitive skin (SS) is associated with discomfort, including burning, stinging, and itching. These symptoms are often exacerbated by environmental factors and personal care products. In this genome-wide association study (GWAS), we aimed to identify the genetic variants associated with SS in 1690 Korean female participants; 389 and 1301 participants exhibited sensitive and non-sensitive skin, respectively. Using a combination of self-reported questionnaires, patch tests, and sting tests, we selected 115 sensitive and 181 non-sensitive participants for genetic analysis. A GWAS was performed to identify the loci associated with SS. Although none of the single-nucleotide polymorphisms (SNPs) met the genome-wide significance threshold, we identified several SNPs with suggestive associations. SNP rs11689992 in the 2q11.3 region increased SS risk by approximately 3.67 times. SNP rs7614738 in the USP4 locus elevated SS risk by 2.34 times and was found to be an expression quantitative trait locus for GPX1, a gene involved in oxidative stress and inflammation. Additionally, SNPs rs12306124 in the RASSF8 locus and rs10483893 in the NRXN3 region were identified. These results suggest that the genetic variations affecting oxidative stress, cell growth regulation, and neurobiology potentially influence skin sensitivity, providing a basis for further investigation and the development of personalized approaches to manage sensitive skin. Full article

Recent studies have highlighted the therapeutic potential of stem cells for various diseases. However, unlike other tissues, brain tissue has a specific structure, consisting of synapses. These synapses not only transmit but also process and refine information. Therefore, synaptic regeneration plays a key role in therapy of neurodegenerative disorders. Neurexins (NRXNs) and neuroligins (NLGNs) are synaptic cell adhesion molecules that connect pre- and postsynaptic neurons at synapses, mediate trans-synaptic signaling, and shape neural network properties by specifying synaptic functions. In this study, we investigated the synaptic regeneration effect of human neural stem cells (NSCs) overexpressing NRXNs (F3.NRXN) and NLGNs (F3.NLGN) in a spinal cord injury model. Overexpression of NRXNs and NLGNs in the neural stem cells upregulated the expression of synaptophysin, PSD95, VAMP2, and synapsin, which are synaptic markers. The BMS scores indicated that the transplantation of F3.NRXN and F3.NLGN enhanced the recovery of locomotor function in adult rodents following spinal cord injury. Transplanted F3.NRXN and F3.NLGN differentiated into neurons and formed a synapse with the host cells in the spinal cord injury mouse model. In addition, F3.NRXN and F3.NLGN cells restored growth factors (GFs) and neurotrophic factors (NFs) and induced the proliferation of host cells. This study suggested that NSCs overexpressing NRXNs and NLGNs could be candidates for cell therapy in spinal cord injuries by facilitating synaptic regeneration. Full article

Down syndrome (DS) is the most common form of inherited intellectual disability caused by trisomy of chromosome 21, presenting with intellectual impairment, craniofacial abnormalities, cardiac defects, and gastrointestinal disorders. The Ts65Dn mouse model replicates many abnormalities of DS. We hypothesized that investigation of the cerebral cortex of fluoxetine-treated trisomic mice may provide proteomic signatures that identify therapeutic targets for DS. Subcellular fractionation of synaptosomes from cerebral cortices of age- and brain-area-matched samples from fluoxetine-treated vs. water-treated trisomic and euploid male mice were subjected to HPLC-tandem mass spectrometry. Analysis of the data revealed enrichment of trisomic risk genes that participate in regulation of synaptic vesicular traffic, pre-synaptic and post-synaptic development, and mitochondrial energy pathways during early brain development. Proteomic analysis of trisomic synaptic fractions revealed significant downregulation of proteins involved in synaptic vesicular traffic, including vesicular endocytosis (CLTA, CLTB, CLTC), synaptic assembly and maturation (EXOC1, EXOC3, EXOC8), anterograde axonal transport (EXOC1), neurotransmitter transport to PSD (SACM1L), endosomal-lysosomal acidification (ROGDI, DMXL2), and synaptic signaling (NRXN1, HIP1, ITSN1, YWHAG). Additionally, trisomic proteomes revealed upregulation of several trafficking proteins, involved in vesicular exocytosis (Rab5B), synapse elimination (UBE3A), scission of endocytosis (DBN1), transport of ER in dendritic spines (MYO5A), presynaptic activity-dependent bulk endocytosis (FMR1), and NMDA receptor activity (GRIN2A). Chronic fluoxetine treatment of Ts65Dn mice rescued synaptic vesicular abnormalities and prevented abnormal proteomic changes in adult Ts65Dn mice, pointing to therapeutic targets for potential treatment of DS. Full article

Background: Autism spectrum disorder (ASD) is a complex neurodevelopmental condition characterized by social communication challenges and repetitive behaviors. Recent research has increasingly focused on the genetic underpinnings of ASD, with the Neurexin 1 (NRXN1) gene emerging as a key player. This comprehensive systematic review elucidates the contribution of NRXN1 gene variants in the pathophysiology of ASD. Methods: The protocol for this systematic review was designed a priori and was registered in the PROSPERO database (CRD42023450418). A risk of bias analysis was conducted using the Joanna Briggs Institute (JBI) critical appraisal tool. We examined various studies that link NRXN1 gene disruptions with ASD, discussing both the genotypic variability and the resulting phenotypic expressions. Results: Within this review, there was marked heterogeneity observed in ASD genotypic and phenotypic manifestations among individuals with NRXN1 mutations. The presence of NRXN1 mutations in this population emphasizes the gene’s role in synaptic function and neural connectivity. Conclusion: This review not only highlights the role of NRXN1 in the pathophysiology of ASD but also highlights the need for further research to unravel the complex genetic underpinnings of the disorder. A better knowledge about the multifaceted role of NRXN1 in ASD can provide crucial insights into the neurobiological foundations of autism and pave the way for novel therapeutic strategies. Full article

Glioblastoma (GBM) is one of the most progressive and prevalent cancers of the central nervous system. Identifying genetic markers is therefore crucial to predict prognosis and enhance treatment effectiveness in GBM. To this end, we obtained gene expression data of GBM from TCGA and GEO datasets and identified differentially expressed genes (DEGs), which were overlapped and used for survival analysis with univariate Cox regression. Next, the genes’ biological significance and potential as immunotherapy candidates were examined using functional enrichment and immune infiltration analysis. Eight prognostic-related DEGs in GBM were identified, namely CRNDE, NRXN3, POPDC3, PTPRN, PTPRN2, SLC46A2, TIMP1, and TNFSF9. The derived risk model showed robustness in identifying patient subgroups with significantly poorer overall survival, as well as those with distinct GBM molecular subtypes and MGMT status. Furthermore, several correlations between the expression of the prognostic genes and immune infiltration cells were discovered. Overall, we propose a survival-derived risk score that can provide prognostic significance and guide therapeutic strategies for patients with GBM. Full article

Mutations in the Neuroligin-3 (Nlgn3) gene are implicated in autism spectrum disorder (ASD) and gastrointestinal (GI) dysfunction, but cellular Nlgn3 expression in the enteric nervous system remains to be characterised. We combined RNAScope in situ hybridization and immunofluorescence to measure Nlgn3 mRNA expression in cholinergic and VIP-expressing submucosal neurons, nitrergic and calretinin-containing myenteric neurons and glial cells in both WT and Nlgn3^R451C mutant mice. We measured Nlgn3 mRNA neuronal and glial expression via quantitative three-dimensional image analysis. To validate dual RNAScope/immunofluorescence data, we interrogated available single-cell RNA sequencing (scRNASeq) data to assess for Nlgn3, Nlgn1, Nlgn2 and their binding partners, Nrxn1-3, MGDA1 and MGDA2, in enteric neural subsets. Most submucosal and myenteric neurons expressed Nlgn3 mRNA. In contrast to other Nlgns and binding partners, Nlgn3 was strongly expressed in enteric glia, suggesting a role for neuroligin-3 in mediating enteric neuron–glia interactions. The autism-associated R451C mutation reduces Nlgn3 mRNA expression in cholinergic but not in VIPergic submucosal neurons. In the myenteric plexus, Nlgn3 mRNA levels are reduced in calretinin, nNOS-labelled neurons and S100 β -labelled glia. We provide a comprehensive cellular profile for neuroligin-3 expression in ileal neuronal subpopulations of mice expressing the R451C autism-associated mutation in Nlgn3, which may contribute to the understanding of the pathophysiology of GI dysfunction in ASD. Full article

Background: Heterozygous, large-scale deletions at 14q24.3-31.1 affecting the neurexin-3 gene have been associated with neurodevelopmental disorders such as autism. Both “de novo” occurrences and inheritance from a healthy parent suggest incomplete penetrance and expressivity, especially in autism spectrum disorder. NRXN3 encodes neurexin-3, a neuronal cell surface protein involved in cell recognition and adhesion, as well as mediating intracellular signaling. NRXN3 is expressed in two distinct isoforms (alpha and beta) generated by alternative promoters and splicing. MM/Results: Using exome sequencing, we identified a monoallelic frameshift variant c.159_160del (p.Gln54AlafsTer50) in the NRXN3 beta isoform (NM_001272020.2) in a 5-year-old girl with developmental delay, autism spectrum disorder, and behavioral issues. This variant was inherited from her mother, who did not have any medical complaints. Discussion: This is the first detailed report of a loss-of-function variant in NRXN3 causing an identical phenotype, as reported for heterozygous large-scale deletions in the same genomic region, thereby confirming NRXN3 as a novel gene for neurodevelopmental disorders with autism. Full article

The 3′ untranslated region has an important role in gene regulation through microRNAs, and it has been estimated that microRNAs regulate up to 50% of coding genes in mammals. With the aim of allelic variant identification of 3′ untranslated region microRNA seed sites, the 3′ untranslated region was searched for seed sites of four temperament-associated genes (CACNG4, EXOC4, NRXN3, and SLC9A4). The microRNA seed sites were predicted in the four genes, and the CACNG4 gene had the greatest number with 12 predictions. To search for variants affecting the predicted microRNA seed sites, the four 3′ untranslated regions were re-sequenced in a Brahman cattle population. Eleven single nucleotide polymorphisms were identified in the CACNG4, and eleven in the SLC9A4. Rs522648682:T>G of the CACNG4 gene was located at the predicted seed site for bta-miR-191. Rs522648682:T>G evidenced an association with both exit velocity (p = 0.0054) and temperament score (p = 0.0097). The genotype TT had a lower mean exit velocity (2.93 ± 0.4 m/s) compared with the TG and GG genotypes (3.91 ± 0.46 m/s and 3.67 ± 0.46 m/s, respectively). The allele associated with the temperamental phenotype antagonizes the seed site, disrupting the bta-miR-191 recognition. The G allele of CACNG4-rs522648682 has the potential to influence bovine temperament through a mechanism associated with unspecific recognition of bta-miR-191. Full article

The cell adhesion molecule L1 is essential not only for neural development, but also for synaptic functions and regeneration after trauma in adulthood. Abnormalities in L1 functions cause developmental and degenerative disorders. L1’s functions critically depend on proteolysis which underlies dynamic cell interactions and signal transduction. We showed that a 70 kDa fragment (L1-70) supports mitochondrial functions and gene transcription. To gain further insights into L1-70’s functions, we investigated several binding partners. Here we show that L1-70 interacts with topoisomerase 1 (TOP1), peroxisome proliferator-activated receptor γ (PPARγ) and NADH dehydrogenase (ubiquinone) flavoprotein 2 (NDUFV2). TOP1, PPARγ and NDUFV2 siRNAs reduced L1-dependent neurite outgrowth, and the topoisomerase inhibitors topotecan and irinotecan inhibited L1-dependent neurite outgrowth, neuronal survival and migration. In cultured neurons, L1 siRNA reduces the expression levels of the long autism genes neurexin-1 (Nrxn1) and neuroligin-1 (Nlgn1) and of the mitochondrially encoded gene NADH:ubiquinone oxidoreductase core subunit 2 (ND2). In mutant mice lacking L1-70, Nrxn1 and Nlgn1, but not ND2, mRNA levels are reduced. Since L1-70’s interactions with TOP1, PPARγ and NDUFV2 contribute to the expression of two essential long autism genes and regulate important neuronal functions, we propose that L1 may not only ameliorate neurological problems, but also psychiatric dysfunctions. Full article

The polygenic nature of schizophrenia (SCZ) implicates many variants in disease development. Rare variants of high penetrance have been shown to contribute to the disease prevalence. Whole-exome sequencing of a large three-generation family with SCZ and bipolar disorder identified a single segregating novel, rare, non-synonymous variant in the gene CASKIN1. The variant D1204N is absent from all databases, and CASKIN1 has a gnomAD missense score Z = 1.79 and pLI = 1, indicating its strong intolerance to variation. We find that introducing variants in the proline-rich region where the D1204N resides results in significant cellular changes in iPSC-derived neurons, consistent with CASKIN1’s known functions. We observe significant transcriptomic changes in 368 genes (padj < 0.05) involved in neuronal differentiation and nervous system development. We also observed nominally significant changes in the frequency of action potentials during differentiation, where the speed at which the edited and unedited cells reach the same level of activity differs. Our results suggest that CASKIN1 is an excellent gene candidate for psychosis development with high penetrance in this family. Full article

Prion gene (PRNP) mutations are associated with diverse disease phenotypes, including familiar Creutzfeldt–Jakob Disease (CJD), Gerstmann–Sträussler–Scheinker disease (GSS), and fatal familial insomnia (FFI). Interestingly, PRNP mutations have been reported in patients diagnosed with Alzheimer’s disease, dementia with Lewy bodies, Parkinson’s disease, and frontotemporal dementia. In this review, we describe prion mutations in Asian countries, including Republic of Republic of Korea, China, and Japan. Clinical phenotypes and imaging data related to these mutations have also been introduced in detail. Several prion mutations are specific to Asians and have rarely been reported in countries outside Asia. For example, PRNP V180I and M232R, which are rare in other countries, are frequently detected in Republic of Korea and Japan. PRNP T188K is common in China, and E200K is significantly more common among Libyan Jews in Israel. The A117V mutation has not been detected in any Asian population, although it is commonly reported among European GSS patients. In addition, V210I or octapeptide insertion is common among European CJD patients, but relatively rare among Asian patients. The reason for these differences may be geographical or ethical isolation. In terms of clinical phenotypes, V180I, P102L, and E200K present diverse clinical symptoms with disease duration, which could be due to other genetic and environmental influences. For example, rs189305274 in the ACO1 gene may be associated with neuroprotective effects in cases of V180I mutation, leading to longer disease survival. Additional neuroprotective variants may be possible in cases featuring the E200K mutation, such as KLKB1, KARS, NRXN2, LAMA3, or CYP4X1. E219K has been suggested to modify the disease course in cases featuring the P102L mutation, as it may result in the absence of prion protein-positive plaques in tissue stained with Congo red. However, these studies analyzed only a few patients and may be too preliminary. The findings need to be verified in studies with larger sample sizes or in other populations. It would be interesting to probe additional genetic factors that cause disease progression or act as neuroprotective factors. Further studies are needed on genetic modifiers working with prions and alterations from mutations. Full article