Synapsin Research Articles

Common SYNE2 Genetic Variant Associated With Atrial Fibrillation Lowers Expression of Nesprin-2α1 With Downstream Effects on Nuclear and Electrophysiological Traits.

Atrial fibrillation GWAS (genome-wide association studies) identified significant associations for rs1152591 and linked variants in the SYNE2 gene encoding Nesprin-2, which connects the nuclear membrane with the cytoskeleton. Reporter gene vector transfection and CRISPR-Cas9 editing were used to identify the causal variant regulating the expression of SYNE2α1. After SYNE2 knockdown or SYNE2α1 overexpression in human stem cell-derived cardiomyocytes, nuclear phenotypes were assessed by imaging and atomic force microscopy. Gene expression was assessed by RNAseq and gene set enrichment analysis. Fura-2 AM staining assessed calcium transients. Optical mapping assessed action potential duration and conduction velocity. The risk allele of rs1152591 had lower promoter and enhancer activity and was significantly associated with lower expression of the short SYNE2α1 isoform in human stem cell-derived cardiomyocytes, without an effect on the expression of the full-length SYNE2 mRNA. SYNE2α1 overexpression had dominant negative effects on the nucleus with its overexpression or SYNE2 knockdown leading to increased nuclear area and decreased nuclear stiffness. Gene expression results from SYNE2α1 overexpression demonstrated both concordant and nonconcordant effects with SYNE2 knockdown. SYNE2α1 overexpression had a gain of function on electrophysiology, leading to significantly faster calcium reuptake and decreased assessed action potential duration, while SYNE2 knockdown showed both shortened assessed action potential duration and decreased conduction velocity. rs1152591 was identified as a causal atrial fibrillation variant, with the risk allele decreasing SYNE2α1 expression. Downstream effects of SYNE2α1 overexpression include changes in nuclear stiffness and electrophysiology, which may contribute to the mechanism for the risk allele's association with AF.

Identification of an intronic Alu insertion in the SYNE1 gene associated with autosomal recessive spinocerebellar ataxia type 8

Identification of an intronic Alu insertion in the SYNE1 gene associated with autosomal recessive spinocerebellar ataxia type 8

Genetic investigation of patients with autosomal recessive ataxia and identification of two novel variants in the SQSTM1 and SYNE1 genes

Hereditary ataxias are classified by inheritance patterns into autosomal dominant, autosomal recessive, X-linked, and mitochondrial modes of inheritance. A large group of adult hereditary ataxias have autosomal dominant inheritance, and autosomal recessive cerebellar ataxias (ARCAs) are rare, with greater diversity in phenotypic and genotypic features. Therefore, comprehensive genetic testing is useful for identifying the genes responsible for ARCAs. We identified two novel pathogenic variants of the SQSTM1 and SYNE1 genes via whole-exome sequencing in patients with ARCAs.

Early-Life Exposure to 4-Hydroxy-4'-Isopropoxydiphenylsulfone Induces Behavioral Deficits Associated with Autism Spectrum Disorders in Mice.

Exposure to bisphenol A (BPA) during gestation and lactation is considered to be a potential risk factor for autism spectrum disorder (ASD) in both humans and animals. As a novel alternative to BPA, 4-hydroxy-4'-isopropoxydiphenylsulfone (BPSIP) is frequently detected in breast milk and placental barrier systems, suggesting potential transmission from the mother to offspring and increased risk of exposure. Gestation and lactation are critical periods for central nervous system development, which are vulnerable to certain environmental pollutants. Herein, we investigated the behavioral impacts and neurobiological effects of early-life exposure to BPSIP (0.02, 0.1, and 0.5 mg/kg body weight/day) in mice offspring. Behavioral studies indicated that BPSIP exposure induced ASD-like behaviors, including elevated anxiety-related behavior and decreased spatial memory, in both male and female pups. A distinct pattern of reduced social novelty was observed only in female offspring, accompanied by significant alterations in antioxidant levels. Transcriptome analysis demonstrated that differentially expressed genes (DEGs) were mainly enriched in pathways related to behaviors and neurodevelopment, which were consistent with the observed phenotype. Besides, a decrease in the protein levels of complex IV (COX IV) across all tested populations suggests a profound impact on mitochondrial function, potentially leading to abnormal energy metabolism in individuals with autism. Additionally, changes in synaptic proteins, evidenced by alterations in synapsin 1 (SYN1) and postsynaptic density protein-95 (PSD95) levels in the cerebellum and hippocampus, support the notion of synaptic involvement. These findings suggest that BPSIP may induce sex-specific neurotoxic effects that involve oxidative stress, energy generation, and synaptic plasticity.

Electro-Clinical Features and Functional Connectivity Analysis in SYN1-Related Epilepsy.

There is currently scarce data on the electroclinical characteristics of epilepsy associated with synapsin 1 (SYN1) pathogenic variations. We examined clinical and electro-encephalographic (EEG) features in patients with epilepsy and SYN1 variants, with the aim of identifying a distinctive electroclinical pattern. In this retrospective multicenter study, we collected and reviewed demographic, genetic, and epilepsy data of 19 male patients with SYN1 variants. Specifically, we analyzed interictal EEG data for all patients, and electro-clinical data from 10 epileptic seizures in 5 patients, using prolonged video-EEG monitoring recordings. Inter-ictal EEG functional connectivity parameters and frequency spectrum of the 10 patients over 12 years of age, were computed and compared with those of 56 age- and sex-matched controls. The main electroclinical features of epilepsy in patients with SYN1 were (1) EEG background and organization mainly normal; (2) interictal abnormalities are often rare or not visible on EEG; (3) more than 60% of patients had reflex seizures (cutaneous contact with water and defecation being the main triggers) isolated or associated with spontaneous seizures; (4) electro-clinical semiology of seizures was mainly temporal or temporo-insulo/perisylvian with a notable autonomic component; and (5) ictal EEG showed a characteristic rhythmic theta/delta activity predominating in temporo-perisylvian regions at the beginning of most seizures. Comparing patients with SYN1 to healthy subjects, we observed a shift to lower frequency bands in power spectrum of interictal EEG and an increased connectivity in both temporal regions. A distinct epilepsy syndrome emerges in patients with SYN1, with a rather characteristic clinical and EEG pattern suggesting predominant temporo-insular involvement. ANN NEUROL 2024.

Differential transcriptome study on the damage of testicular tissues caused by chronic infection of T. gondii in mice

BackgroundToxoplasma gondii is an intracellular protozoan parasite that is widely distributed in humans and warm-blooded animals. T. gondii chronic infections can cause toxoplasmic encephalopathy, adverse pregnancy, and male reproductive disorders. In male reproduction, the main function of the testis is to provide a stable place for spermatogenesis and immunological protection. The disorders affecting testis tissue encompass abnormalities in the germ cell cycle, spermatogenic retardation, or complete cessation of sperm development. However, the mechanisms of interaction between T. gondii and the reproductive system is unclear. The aims were to study the expression levels of genes related to spermatogenesis, following T. gondii infection, in mouse testicular tissue.MethodsRNA-seq sequencing was carried out on mouse testicular tissues from mice infected or uninfected with the T. gondii type II Prugniaud (PRU) strain and validated in combination with real-time quantitative PCR and immunofluorescence assays.ResultsThe results showed that there were 250 significant differentially expressed genes (DEGs) (P < 0.05, |log2fold change| ≧ 1). Bioinformatics analysis showed that 101 DEGs were annotated to the 1696 gene ontology (GO) term. While there was a higher number of DEGs in the biological process classification as a whole, the GO enrichment revealed a significant presence of DEGs in the cellular component classification. The Arhgap18 and Syne1 genes undergo regulatory changes following T. gondii infection, and both were involved in shaping the cytoskeleton of the blood–testis barrier (BTB). The number of DEGs enriched in the MAPK signaling pathway, the ERK1/2 signaling pathway, and the JNK signaling pathway were significant. The PTGDS gene is located in the Arachidonic acid metabolism pathway, which plays an important role in the formation and maintenance of BTB in the testis. The expression of PTGDS is downregulated subsequent to T. gondii infection, potentially exerting deleterious effects on the integrity of the BTB and the spermatogenic microenvironment within the testes.ConclusionsOverall, our research provides in-depth insights into how chronic T. gondii infection might affect testicular tissue and potentially impact male fertility. These findings offer a new perspective on the impact of T. gondii infection on the male reproductive system.Graphical

Hierarchical learning of gastric cancer molecular subtypes by integrating multi‐modal DNA‐level omics data and clinical stratification

Hierarchical learning of gastric cancer molecular subtypes by integrating multi‐modal DNA‐level omics data and clinical stratification

SYNE1 gene mutation: A recessive ataxic syndrome presenting with weakness and muscle atrophy. A case report

BackgroundAutosomal recessive spinocerebellar ataxia type 8 (SCAR8) is a rare neurodegenerative disease that can be manifest in a wide spectrum from ataxias and motoneuron syndromes. ObjectiveTo report a case of mutation in the SYNE1 gene with predominant motoneuron disease signs. MethodsIndex case medical report and literature review. ResultsA 32-year-old woman onset with pyramidal and lower motoneuron signs and symptoms during the second decade of life, with marked dysarthria showing associated cerebellar pattern. Clinical investigation with electroneuromyography showed chronic preganglionic disease and brain MRI showed cerebellar atrophy. Genetic testing confirmed pathogenic mutation in homozygosity in the SYNE1 gene. ConclusionsRare neurological condition that may be associated with signs of impairment of the pyramidal pathway and second motoneuron (amyotrophic lateral sclerosis-like syndrome), in addition to cerebellar ataxia in insidious course.

Effects of autotaxin and lysophosphatidic acid deficiencies on depression-like behaviors in mice exposed to chronic unpredictable mild stress

The involvement of lipids in the mechanism of depression has triggered extensive discussions. Earlier studies have identified diminished levels of lysophosphatidic acid (LPA) and autotaxin (ATX) in individuals experiencing depression. However, the exact significance of this phenomenon in relation to depression remains inconclusive. This study seeks to explore the deeper implications of these observations. We assessed alterations in ATX and LPA in both the control group and the chronic unpredictable mild stress (CUMS) model group. Additionally, the impact of ATX adeno-associated virus (AAV-ATX) injection into the hippocampus was validated through behavioral tests in CUMS-exposed mice. Furthermore, we probed the effects of LPA on synapse-associated proteins both in HT22 cells and within the mouse hippocampus. The mechanisms underpinning the LPA-triggered shifts in protein expression were further scrutinized. Hippocampal tissues were augmented with ATX to assess its potential to alleviate depression-like behavior by modulating synaptic-related proteins. Our findings suggest that the decrement in ATX and LPA levels alters the expression of proteins associated with synaptic plasticity in vitro and in vivo, such as synapsin-I (SYN), synaptophysin (SYP), and brain-derived neurotrophic factor (BDNF). Moreover, we discerned a role for the ERK/CREB signaling pathway in mediating the effects of ATX and LPA. Importantly, strategic supplementation of ATX effectively mitigated depression-like behaviors. This study indicates that the ATX-LPA pathway may influence depression-like behaviors by modulating synaptic plasticity in the brains of CUMS-exposed mice. These insights augment our understanding of depression's potential pathogenic mechanism in the context of lipid metabolism and propose promising therapeutic strategies for ameliorating the disease.

Nesprin1 Deficiency Is Associated with Poor Prognosis of Renal Cell Carcinoma and Resistance to Sunitinib Treatment

Introduction: Nuclear envelope spectrin repeat protein (Nesprin) 1 encoded by SYNE1, crucially regulates the morphology and functions of the cell. Mutations in the SYNE1 gene are associated with various diseases; however, their significance in renal cell carcinoma (RCC) remains unknown. In this study, we have investigated the association of SYNE1/Nesprin1 with the progression and prognosis of clear cell RCC (ccRCC). Methods: In silico analyses of publicly available datasets of patients with RCC were performed. Based on the cohort data, Nesprin1 expression in nephrectomized tissue samples acquired from patients with ccRCC was analyzed using immunohistochemical staining. The invasion, migration, and proliferation of the SYNE1-knockdown human RCC cell lines were analyzed in vitro; moreover, RNA sequencing and gene set enrichment analysis were conducted to study the molecular mechanism underlying the association of SYNE1/Nesprin1 with prognosis of RCC. Results: Patients with RCC-associated SYNE1 gene mutations exhibited significantly worse overall and progression-free survivals. Patients with Nesprin1-negative ccRCC tumors exhibit significantly poorer overall, cancer-specific, and recurrence-free survival rates than those recorded in the Nesprin1-positive group. SYNE1 knockdown enhanced the invasion and migration of RCC cells; however, it did not influence the proliferation of cells. RNA sequencing and gene set enrichment analysis revealed that SYNE1 knockdown significantly altered the expression of genes associated with oxidative phosphorylation. Consistently, patients with RCC exhibiting low SYNE1 expression, who were treated with the vascular endothelial growth factor receptor inhibitor sunitinib, had worse progression-free survival. Conclusions: The results indicate that the expression of SYNE1/Nesprin1 and SYNE1 mutations in patients with RCC are closely linked to their prognosis and responsiveness to sunitinib treatment.

Lead exposure induced transgenerational developmental neurotoxicity by altering genome methylation in Drosophila melanogaster

Heavy metal toxicity is a significant global health concern, with particular attention given to lead (Pb) exposure due to its adverse effects on cognitive development, especially in children exposed to low concentrations. While Pb neurotoxicity has been extensively studied, the analysis and molecular mechanisms underlying the transgenerational effects of Pb exposure-induced neurotoxicity remain poorly understood. In this study, we utilized Drosophila, a powerful developmental animal model, to investigate this phenomenon. Our findings demonstrated that Pb exposure during the developmental stage had a profound effect on the neurodevelopment of F0 fruit flies. Specifically, we observed a loss of correlation between the terminal motor area and muscle fiber area, along with an increased frequency of the β-lobe midline crossing phenotype in mushroom bodies. Western blot analysis indicated altered expression levels of synaptic vesicle proteins, with a decrease in Synapsin (SYN) and an increase in Bruchpilot (BRP) expression, suggesting changes in synaptic vesicle release sites. These findings were corroborated by electrophysiological data, showing an increase in the amplitude of evoked excitatory junctional potential (EJP) and an increase in the frequency of spontaneous excitatory junctional potential (mEJP) following Pb exposure. Importantly, our results further confirmed that the developmental neurotoxicity resulting from grandparental Pb exposure exhibited a transgenerational effect. The F3 offspring displayed neurodevelopmental defects, synaptic function abnormalities, and repetitive behavior despite lacking direct Pb exposure. Our MeDIP-seq analysis further revealed significant alterations in DNA methylation levels in several neurodevelopmental associated genes (eagle, happyhour, neuroglian, bazooka, and spinophilin) in the F3 offspring exposed to Pb. These findings suggest that DNA methylation modifications may underlie the inheritance of acquired phenotypic traits resulting from environmental Pb exposure.

Rare forms of autosomal recessive spinocerebellar ataxia associated with mutations in the ANO10 (ATX-ANO10) and SYNE1 (ATX-SYNE1) genes

To analyze clinical and genetic characteristics of patients with the verified rare forms of autosomal recessive spinocerebellar ataxias, ATX-ANO10 and ATX-SYNE1. Six unrelated patients with established diagnoses were examined: 4 patients with ATX-ANO10 and 2 patients with ATX-SYNE1. Brain MRI and nerve conduction study were performed. To screen for cognitive impairment, the scale for the Assessment and Rating of Ataxia (SARA), and the Montreal Cognitive Assessment Scale (MoCA) were used. Mutation screening included panel sequencing on the Illumina MiSeq platform. Six variants were found in the ANO10 gene: the previously described pathogenic nonsense mutations c.G1025A (p.W342X) and c.C1244G (p.S415X), as well as novel probably pathogenic variants c.1477-2A>G and c.G101T (p.W34L) and missense mutations c.A110C (p.N37T) and c.T104C (p.L35P) of undetermined significance. A novel nonsense mutation c.C8911T (p.Q2971X) and a previously described pathogenic variant c.C4939T (p.Q1647X) were found in the SYNE1 gene. The clinical presentation of the ATX-ANO10 and ATX-SYNE1 was typical presenting with slowly progressive cerebellar ataxia with pyramidal signs, with young onset and cerebellar atrophy according to brain MRI study. We provided first-ever data on clinical features and mutation spectrum In Russian patients with ATX-ANO10 and ATX-SYNE1. The phenotype of these ataxias is nonspecific, so the method of choice for molecular diagnostics is massive parallel sequencing.

SYNE1 gene novel variant is associated with myocardial infarction in young people with a family history of premature atherosclerosis

Abstract Introduction Genetic background is thought to be responsible for a family occurred premature atherosclerosis, including myocardial infarction (MI). Purpose The aim of the study was to investigate the role of genetic variants in young patients (aged &amp;lt;50 years) with MI and family history of premature atherosclerosis. Methods The studied group consisted of 70 patients aged 26-49 (mean 43.1, SD ±4.3), 17 women and 53 men, with MI and with family history of premature atherosclerosis, defined as MI or ischaemic stroke in first-degree relatives at age &amp;lt;65 years in women or &amp;lt;55 years in men. The mean BMI in the studied group was 28.8 kg/m2 (SD ±3.5), total cholesterol level 202.3 mg/dl (SD ±3.5), HDL 40.6 mg/dl (SD ±9.6), LDL 124.0 mg/dl (SD ±28.9), triglycerides 164.4 mg/dl (SD ±63.5), glucose 108.3 mg/dl (SD ±19.9) and creatinine 0.9 mg/dl (SD ±0.2). Regarding other risk factors 63 patients (90%) were smokers (mean 24.1 pack-years, SD ±13.0), 44 (62.8%) had hypertension, 11 (15.7%) had diabetes mellitus, and 8 (11.4%) had depression. All patients had diagnosed MI including MI with ST elevation (STEMI) in 18 cases (25.7%) and MI without ST elevation (NSTEMI) in 52 cases (74.3%). All patients, except 2 (no consent), had performed coronary angiography revealing 1-vessel coronary artery disease (VCAD) in 33 patients (47.1%), 2-VCAD in 17 patients (24.3%), and 3-VCAD in 20 patients (28.6%). The mean left ventricular ejection fraction (LVEF) was 51.8% (SD ±8.0). The total DNA has been extracted from whole peripheral blood samples. The targeted enrichment library was prepared and analyzed using New Generation Sequencing method on Hiseq4000, 2x150 cycles. Statistical analyses were performed using the R software package (www.r-project.org/). The results of sequencing were compared to data from the reference control population consisting of 597 healthy people (418 women, 179 men) aged 18-83 (mean 40.5, SD ± 12,4) as a whole and after matching with a studied group by age and gender in a proportion 1:3 (210 people, 51 women and 159 men, aged 18-77, mean 42.1, SD ±10.6) using Propensity Score Matching. Risks associated with detected variants were evaluated using Fisher’s exact test based on the allelic frequencies of variants in both groups. Results SYNE1 gene variant rs36215567 (NM_182961.4: c.20396+22A&amp;gt;G) has been detected in statistically significant higher incidence in the studied group in comparison to the control population (p=0.005) with OR=4,80 (95%CI 1,43-14,45) as well as when compared to the control population matched by age and gender (p=0.004) OR=9,31 (95%CI 1,64-95,41). There were no statistically significant differences in the incidence of familial hypercholesterolemia related gene variants: LDLR c.667G&amp;gt;A, PCSK9 c.658-36G&amp;gt;A, PCSK9 c.996+55C&amp;gt;A and APOB c.12382G&amp;gt;A between both cohorts. Conclusion A novel variant of SYNE1 gene is associated with myocardial infarction in young age patients with a family history of premature atherosclerosis.

Neuroprotective effect and mechanism of Zuogui Jiangtang Jieyu Formula on diabetes mellitus complicated with depression model rats based on CX3CL1-CX3CR1 axis

Based on the CX3C chemokine ligand 1(CX3CL1)-CX3C chemokine receptor 1(CX3CR1) axis, this study explored the potential mechanism by which Zuogui Jiangtang Jieyu Formula(ZGJTJY) improved neuroinflammation and enhanced neuroprotective effect in a rat model of diabetes mellitus complicated with depression(DD). The DD rat model was established by feeding a high-fat diet combined with streptozotocin(STZ) intraperitoneal injection for four weeks and chronic unpredictable mild stress(CUMS) combined with isolated cage rearing for five weeks. The rats were divided into a control group, a model group, a positive control group, an inhibitor group, and a ZGJTJY group. The open field test and forced swimming test were used to assess the depression-like behaviors of the rats. Enzyme-linked immunosorbent assay(ELISA) was performed to measure the expression levels of the pro-inflammatory cytokines interleukin-1β(IL-1β) and tumor necrosis factor-α(TNF-α) in plasma. Immunofluorescence staining was used to detect the expression of ionized calcium-binding adapter molecule 1(Iba1), postsynaptic density protein-95(PSD95), and synapsin-1(SYN1) in the hippocampus. Hematoxylin-eosin(HE) staining, Nissl staining, and TdT-mediated dUTP nick end labeling(TUNEL) fluorescence staining were performed to assess hippocampal neuronal damage. Western blot was used to measure the expression levels of CX3CL1, CX3CR1, A2A adenosine receptor(A2AR), glutamate receptor 2A(NR2A), glutamate receptor 2B(NR2B), and brain-derived neurotrophic factor(BDNF) in the hippocampus. Compared with the model group, the ZGJTJY group showed improved depression-like behaviors in DD rats, enhanced neuroprotective effect, increased expression of PSD95, SYN1, and BDNF(P&lt;0.01), and decreased expression of Iba1, IL-1β, and TNF-α(P&lt;0.01), as well as the expression of CX3CL1, CX3CR1, A2AR, NR2A, and NR2B(P&lt;0.01). These results suggest that ZGJTJY may exert its neuroprotective effect by inhibiting the CX3CL1-CX3CR1 axis and activation of hippocampal microglia, thereby improving neuroinflammation and abnormal activation of N-methyl-D-aspartate receptor(NMDAR) subunits, and ultimately enhancing the expression of synaptic-related proteins PSD95, SYN1, and BDNF in the hippocampus.

Neuroprotection by Polyherbal Medicine Divya-Medha-Vati Against Scopolamine-Induced Cognitive Impairment Through Modulation of Oxidative Stress, Acetylcholine Activity, and Cell Signaling.

Alzheimer disease is associated with cognitive impairments and neuronal damages. In this study, Scopolamine, a model drug used for the generation of Alzheimer-like symptoms induced cognitive dysfunction in C57BL/6 mice. It also elevated acetylcholine esterase (AcHE) activity, and reduced antioxidant (superoxide dismutase and catalase) activity in cortex tissue. Scop reduced neuronal density and increased pyknotic neurons in hippocampus tissue. In mouse neuroblastoma (Neuro2a) cells, Scop triggered a dose-dependent loss of cell viability and neurite outgrowth reduction. Scop-treated Neuro2a cells showed oxidative stress and reduction in mRNA expression for brain-derived neurotrophic factor (BDNF), nerve growth factor-1 (NGF-1), and Synapsin-1 (SYN-1) genes. Mice treated with Divya-Medha-Vati (DMV), an Ayurvedic polyherbal medicine showed protection against Scop-induced cognitive impairment (Morris Water Maze Escape Latency, and Elevated Plus Maze Transfer Latency). DMV protected against Scop-induced AcHE activity, and loss of antioxidant activities in the mice brain cortex while sustaining neuronal density in the hippocampus region. In the Neuro2a cells, DMV reduced Scop-induced loss of cell viability and neurite outgrowth loss. DMV protected the cells against induction of oxidative stress and promoted mRNA expression of BDNF, NGF-1, and SYN-1 genes. Phytochemical profiling of DMV showed the presence of Withanolide A, Withanolide B, Bacopaside II, Jujubogenin, Apigenin, Gallic acid, Caffeic acid, and Quercetin that are associated with antioxidant and neurostimulatory activities. In conclusion, the study showed that Divya-Medha-Vati was capable of promoting neuronal health and inhibiting Alzheimer-like cognitive dysfunction through enhanced antioxidant activities and modulation of neuronal activities.

Synapsin 1 Ameliorates Cognitive Impairment and Neuroinflammation in Rats with Alzheimer's Disease: An Experimental and Bioinformatics Study.

Alzheimer's disease (AD) is a persistent neuropathological injury that manifests via neuronal/synaptic death, age spot development, tau hyperphosphorylation, neuroinflammation, and apoptosis. Synapsin 1 (SYN1), a neuronal phosphoprotein, is believed to be responsible for the pathology of AD. This study aimed to elucidate the exact role of SYN1 in ameliorating AD and its potential regulatory mechanisms. The AD dataset GSE48350 was downloaded from the GEO database, and SYN1 was focused on differential expression analysis and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. After establishing an AD rat model, they were treated with RNAi lentivirus to trigger SYN1 overexpression. The amelioration of SYN1 in AD-associated behavior was validated using multiple experiments (water maze test and object recognition test). SYN1's repairing effect on the important factors in AD was confirmed by detecting the concentration of inflammatory factors (interleukin (IL)-6, IL-1β, tumor necrosis factor (TNF)-α), neurotransmitters (acetylcholine (ACh), dopamine (DA), and 5-hydroxytryptophan (5-HT)) and markers of oxidative stress (glutathione (GSH), malondialdehyde (MDA), reactive oxygen species (ROS)). Molecular biology experiments (qRT-PCR and western blot) were performed to examine AD-related signaling pathways after SYN1 overexpression. Differential expression analysis yielded a total of 545 differentially expressed genes, of which four were upregulated and 541 were downregulated. The enriched pathways were basically focused on synaptic functions, and the analysis of the protein- protein interaction network focused on the key genes in SYN1. SYN1 significantly improved the spatial learning and memory abilities of AD rats. This enhancement was reflected in the reduced escape latency of the rats in the water maze, the significantly extended dwell time in the third quadrant, and the increased number of crossings. Furthermore, the results of the object recognition test revealed reduced time for rats to explore familiar and new objects. After SYN1 overexpression, the cAMP signaling pathway was activated, the phosphorylation levels of the CREB and PKA proteins were elevated, and the secretion of neurotransmitters such as ACh, DA, and 5-HT was promoted. Furthermore, oxidative stress was suppressed, as supported by decreased levels of MDA and ROS. Regarding inflammatory factors, the levels of IL-6, IL-1β, and TNF-α were significantly reduced in AD rats with SYN1 overexpression. SYN1 overexpression improves cognitive function and promotes the release of various neurotransmitters in AD rats by inhibiting oxidative stress and inflammatory responses through cAMP signaling pathway activation. These findings may provide a theoretical basis for the targeted diagnosis and treatment of AD.

Role of ICAM1 in tumor immunity and prognosis of triple-negative breast cancer.

Treating triple-negative breast cancer (TNBC) is a difficult landscape owing to its short survival times and high risk of metastasis and recurrence among patients. Although involved in tumor invasion and metastasis, the mechanism of action of intercellular adhesion molecule 1 (ICAM1), a trans-membrane glycoprotein, in TNBC is ambiguous. We examined ICAM1's role in TNBC, focusing on its expression, cell survival, mutation, and tumor immunity. Then, a risk score model was created utilizing co-expressed genes associated with ICAM1. According to their respective risk scores, we divided patients into high- and low-risk groups. Immune function, drug susceptibility differences, and somatic variants were analyzed in the high-and low-risk groups. And we used the CMap database to predict potential medications. Then, TNBC cells with low expression of ICAM-1 were co-cultured with PMA-treated THP-1 cells and CD8 T cells. In addition, We detected the expression of PD-1 and CTLA4 of low ICAM-1 expressing TNBC cells when they were cocultured with CD8 T cells. ICAM1 was found to be involved in leukocyte cell adhesion, motility, and immune activation. Patients with low-ICAM1 group had shorter disease-free survival (DFS) than those with high-ICAM1 group. The group with elevated levels of ICAM1 exhibited significantly increased levels of T-cell regulation, quiescence in natural killer (NK) cells, and M1 macrophage. ICAM1 expression was correlated with immune checkpoint drugs. The prognostic ability of the risk score model was found to be superior to that of individual genes. Patients categorized as high-risk exhibited elevated clinical stages, showed higher M1 macrophage numbers, and were able to benefit better from immunotherapy. Individuals belonging to the high-risk group exhibit significantly elevated mutation rates in TP53, TTN, and SYNE1 genes, along with increased TMB and PD-L1 levels and decreased TIDE scores. These findings suggest that immunotherapy may be advantageous for the high-risk group. Furthermore, low expression of ICAM1 was found to promote polarization to M2 macrophages along with T-cell exhaustion. In conclusion, Low ICAM1 expression may be related to immune escape, leading to poor treatment response and a worse prognosis.

The alpha-synuclein oligomers activate nuclear factor of activated T-cell (NFAT) modulating synaptic homeostasis and apoptosis

BackgroundSoluble oligomeric forms of alpha-synuclein (aSyn-O) are believed to be one of the main toxic species in Parkinson’s disease (PD) leading to degeneration. aSyn-O can induce Ca2+ influx, over activating downstream pathways leading to PD phenotype. Calcineurin (CN), a phosphatase regulated by Ca2+ levels, activates NFAT transcription factors that are involved in the regulation of neuronal plasticity, growth, and survival.MethodsHere, using a combination of cell toxicity and gene regulation assays performed in the presence of classical inhibitors of the NFAT/CN pathway, we investigate NFAT’s role in neuronal degeneration induced by aSyn-O.ResultsaSyn-O are toxic to neurons leading to cell death, loss of neuron ramification and reduction of synaptic proteins which are reversed by CN inhibition with ciclosporin-A or VIVIT, a NFAT specific inhibitor. aSyn-O induce NFAT nuclear translocation and transactivation. We found that aSyn-O modulates the gene involved in the maintenance of synapses, synapsin 1 (Syn 1). Syn1 mRNA and protein and synaptic puncta are drastically reduced in cells treated with aSyn-O which are reversed by NFAT inhibition.ConclusionsFor the first time a direct role of NFAT in aSyn-O-induced toxicity and Syn1 gene regulation was demonstrated, enlarging our understanding of the pathways underpinnings synucleinopathies.

Correlation of HIV-Induced Neuroinflammation and Synaptopathy with Impairment of Learning and Memory in Mice with HAND.

Over 38 million people worldwide are living with HIV/AIDS, and more than half of them are affected by HIV-associated neurocognitive disorders (HAND). Such disorders are characterized by chronic neuroinflammation, neurotoxicity, and central nervous system deterioration, which lead to short- or long-term memory loss, cognitive impairment, and motor skill deficits that may show gender disparities. However, the underlying mechanisms remain unclear. Our previous study suggested that HIV-1 infection and viral protein R (Vpr) upregulate the SUR1-TRPM4 channel associated with neuroinflammation, which may contribute to HAND. The present study aimed to explore this relationship in a mouse model of HAND. This study employed the HIV transgenic Tg26 mouse model, comparing Tg26 mice with wildtype mice in various cognitive behavioral and memory tests, including locomotor activity tests, recognition memory tests, and spatial learning and memory tests. The study found that Tg26 mice exhibited impaired cognitive skills and reduced learning abilities compared to wildtype mice, particularly in spatial memory. Interestingly, male Tg26 mice displayed significant differences in spatial memory losses (p < 0.001), while no significant differences were identified in female mice. Consistent with our early results, SUR1-TRPM4 channels were upregulated in Tg26 mice along with glial fibrillary acidic protein (GFAP) and aquaporin 4 (AQP4), consistent with reactive astrocytosis and neuroinflammation. Corresponding reductions in neurosynaptic responses, as indicated by downregulation of Synapsin-1 (SYN1) and Synaptophysin (SYP), suggested synaptopathy as a possible mechanism underlying cognitive and motor skill deficits. In conclusion, our study suggests a possible relationship between SUR1-TRPM4-mediated neuroinflammation and synaptopathy with impairments of learning and memory in mice with HAND. These findings could help to develop new therapeutic strategies for individuals living with HAND.

Hippocampal BAIAP2 prevents chronic mild stress-induced depression-like behaviors in mice.

The pathogenesis of depression is closely related to changes in hippocampal synaptic plasticity; however, the underlying mechanism is still unclear. Brain-specific angiogenesis inhibitor 1-associated protein 2 (BAIAP2), a postsynaptic scaffold protein in excitatory synapses important for synaptic plasticity, is highly expressed in the hippocampus and has been implicated in several psychiatric disorders. However, the role of BAIAP2 in depression remains poorly understood. In the present study, a mouse model of depression was established via exposure to chronic mild stress (CMS). An adeno-associated virus (AAV) vector expressing BAIAP2 was injected into the hippocampal brain region of mice and a BAIAP2 overexpression plasmid was transfected into HT22 cells to upregulate BAIAP2 expression. Depression- and anxiety-like behaviors and dendritic spine density were examined in mice using behavioral tests and Golgi staining, respectively. In vitro, hippocampal HT22 cells were treated with corticosterone (CORT) to simulate the stress state, and the effect of BAIAP2 on CORT-induced cell injury was explored. Reverse transcription-quantitative PCR and western blotting were employed to determine the expression levels of BAIAP2 and those of the synaptic plasticity-related proteins glutamate receptor ionotropic, AMPA 1 (GluA1), and synapsin 1 (SYN1). Mice exposed to CMS exhibited depression- and anxiety-like behaviors accompanied by decreased levels of BAIAP2 in the hippocampus. In vitro, the overexpression of BAIAP2 increased the survival rate of CORT-treated HT22 cells and upregulated the expression of GluA1 and SYN1. Consistent with the in vitro data, the AAV-mediated overexpression of BAIAP2 in the hippocampus of mice significantly inhibited CMS-induced depression-like behavior, concomitant with increases in dendritic spine density and the expression of GluA1 and SYN1 in hippocampal regions. Our findings indicate that hippocampal BAIAP2 can prevent stress-induced depression-like behavior and may be a promising target for the treatment of depression or other stress-related diseases.