Molecular Neurobiology最新文献

Parkinson's disease (PD) is a common neurodegenerative disorder, and neuroinflammation plays a pivotal role in its pathogenesis. T-cell immunoglobulin and mucin-domain-containing molecule 3 (Tim-3) is a crucial immunoregulatory mediator in various diseases; however, its roles and underlying molecular mechanisms in PD remain unclear. We established in vitro and in vivo 1-methyl-4-phenylpyridinium (MPP+)/1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD models in Tim-3-knockout BV2 cells and mice, respectively. Motor function was assessed through behavioral tests, including pole, traction, forced swimming, and open field tests. Immunofluorescence was used to examine dopaminergic neuron loss and glial activation. The expression levels of nuclear factor-kappa B (NF-κB)/nucleotide-binding oligomerization domain-like receptor 3 (NLRP3) pathway components were evaluated by western blotting. Proinflammatory cytokines were measured via enzyme-linked immunosorbent assay (ELISA). Compared with the wild-type, Tim-3 expression was significantly increased in the PD model, and Tim-3 deficiency mitigated MPTP-induced motor deficits, dopaminergic neuron loss, and glial cell activation. Furthermore, Tim-3 deficiency suppressed neuroinflammation by negatively modulating the NF-κB/NLRP3 pathway, thereby downregulating the expression of the proinflammatory cytokines IL-1β, IL-18, IL-6, and TNF-α. These findings indicate that Tim-3 plays a proinflammatory role in PD by regulating the NF-κB/NLRP3 pathway, highlighting Tim-3 as a promising therapeutic target for PD.

A paradigm shift in the understanding of bidirectional interactions between peripheral and central nervous systems is essential for development of rehabilitation and preventive interventions based on physical exercise. Although a causal relationship has not been completely established, modulation of voltage-dependent ion channels (Ca²⁺, Cl^-, K⁺, Na⁺, lactate-, H⁺) in skeletal and neuronal cells provides opportunities to maintain force production during exercise and reduce the risk of disease. However, there are caveats to consider when interpreting the effects of physical exercise on this bidirectional axis, since exercise protocol details (e.g., duration and intensity) have variable effects on this crosstalk. Therefore, an integrative perspective of the skeletal muscle and brain's communication pathway is discussed, and the role of physical exercise on such communication highway is explained in this review.

Realgar is a toxic mineral medicine containing arsenic that is present in many traditional Chinese medicines. It has been reported that the abuse of drugs containing realgar has potential neurotoxicity, but its mechanism of toxicity has not been fully clarified. In this study, we demonstrated that arsenic in realgar promoted mitochondrial fission via UBXD8-mediated DRP1 translocation to the mitochondria and activated mitophagy via PINK1-Parkin, resulting in mitochondrial dysfunction and nerve cell death in the rat cortex. We used PC12 cells and treated them with inorganic arsenic (iAs). Mdivi-1, a mitochondrial fission inhibitor, and the siRNA UBXD8 or PINK1 were used as interventions to verify the precise mechanism by which arsenic affects realgar-induced mitochondrial instability. The results revealed that the arsenic in realgar accumulated in the brain and led to neurobehavioral abnormalities in the rats. We demonstrated that arsenic in realgar-induced high expression of UBXD8 promoted the translocation of DRP1 to the mitochondria, where it underwent phosphorylation, which led to the over-fission of the mitochondria and mitochondria-mediated apoptosis. Moreover, the over-fission of the mitochondria activates mitophagy, which is self-protective but only partially alleviates apoptosis and mitochondria dysfunction. Our findings revealed the crosstalk between mitochondrial fission and mitophagy in realgar-induced neurotoxicity. These results highlight the role of the transposition of DRP1 by UBXD8 in realgar-induced mitochondrial dysfunction and provide new ideas and data for the study of the mechanism of realgar-induced neurotoxicity.

Neuromyelitis optica spectrum disorder (NMOSD) is a severe central nervous system disease primarily characterized by optic neuritis and myelitis, which can result in vision loss and limb paralysis. Current treatment options are limited in their ability to prevent relapses and mitigate disease progression, underscoring the urgent need for new drug targets to develop more effective therapies. The objective of this study is to identify potential drug targets associated with a reduced risk of NMOSD attacks or relapses through Mendelian randomization (MR) analysis, thereby addressing the limitations of existing treatment methods and providing better clinical options for patients. To identify therapeutic targets for NMOSD, a MR analysis was conducted. The cis-expression quantitative trait loci (cis-eQTL, exposure) data were sourced from the eQTLGen consortium, which included a sample size of 31,684. NMOSD (outcome) summary data were obtained from two of the largest independent cohorts: one cohort consisted of 86 NMOSD cases and 460 controls derived from whole-genome sequencing data, while the other cohort included 129 NMOSD patients and 784 controls. We performed a two-sample MR analysis to evaluate the association between single nucleotide polymorphisms (SNPs) and copy number variations with NMOSD. The MR analysis utilized the inverse variance weighted (IVW) method, supplemented by MR-Egger, weighted median, simple mode, and weighted mode methods. Sensitivity analyses were conducted to assess the presence of horizontal pleiotropy and heterogeneity. Colocalization analysis was employed to test whether NMOSD risk and gene expression are driven by common SNPs. Additionally, a phenome-wide association study (PheWAS) was performed to detect disease outcomes associated with NEU1. Supplementary analyses included single-nucleus RNA sequencing (snRNA-seq) data analysis, protein-protein interaction (PPI) networks, and drug feasibility assessments to prioritize potential therapeutic targets. Two drug targets, COL4A1 and NEU1, demonstrated significant MR results in two independent datasets. Notably, NEU1 showed substantial evidence of colocalization with NMOSD. Additionally, apart from the association between NEU1 and NMOSD, no other associations were observed between gene-proxied NEU1 inhibition and the increased risk of other NMOSD-related diseases. This study supports the potential of targeting NEU1 for drug inhibition to reduce the risk of NMOSD. Further preclinical research and drug development are warranted to validate the efficacy and safety of NEU1 as a therapeutic target and to explore its potential in NMOSD treatment.

Secreted and membrane-tethered mammalian neuromodulators from the Ly6/uPAR family are involved in regulation of many physiological processes. Some of them are expressed in the CNS in the neurons of different brain regions and target neuronal membrane receptors. Thus, Lynx1 potentiates nicotinic acetylcholine receptors (nAChRs) in the brain, while others like Lypd6 and Lypd6b suppress it. However, the mechanisms underlying the regulation of cognitive processes by these neuromodulators remain unclear. Here, we showed that water-soluble analogue of Lynx1 (ws-Lynx-1) targets α7-nAChRs both in the hippocampal neurons and astrocytes. Incubation of astrocytes with ws-Lynx1 increased expression of connexins 30 and 43; α4, α5, and β4 integrins; and E- and P-cadherins. Ws-Lynx1 reduced secretion of pro-inflammatory adhesion factors ICAM-1, PSGL-1, and VCAM-1 and downregulated secretion of CD44 and NCAM, which inhibit synaptic plasticity. Moreover, increased astrocytic secretion of the dendritic growth activator ALCAM and neurogenesis regulator E-selectin was observed. Incubation of neurons with ws-Lynx1 potentiated α7-nAChRs and upregulated dendritic spine density. Thus, the pro-cognitive activity of ws-Lynx1 observed previously can be explained by stimulation of astrocytic network and signaling together with up-regulation of spinogenesis, potentiation of the α7-nAChRs, and neuronal and synaptic plasticity. For comparison, influence of water-soluble analogues of a set of Ly6/uPAR proteins (SLURP-1, SLURP-2, Lypd6, Lypd6b, and PSCA) on dendritic spine density and diameter was studied. Data obtained give new insights on the role of Ly6/uPAR proteins in the brain and open new prospects for the development of drugs to improve cognitive function.

Cardiolipin (CL) is an essential phospholipid that supports the functions of mitochondrial membrane transporters and oxidative phosphorylation complexes. Due to the high level of fatty acyl chain unsaturation, CL is prone to peroxidation during aging, neurodegenerative disease, stroke, and traumatic brain or spinal cord injury. Therefore, effective therapies that stabilize and preserve CL levels or enhance healthy CL fatty acyl chain remodeling are needed. In the last few years, great strides have been made in determining the mechanisms through which precursors for CL biosynthesis, such as phosphatidic acid (PA), are transferred from the ER to the outer mitochondrial membrane (OMM) and then to the inner mitochondrial membrane (IMM) where CL biosynthesis takes place. Many neurodegenerative disorders show dysfunctional mitochondrial ER contact sites that may perturb PA transport and CL biosynthesis. However, little is currently known on how neuronal mitochondria regulate the synthesis, remodeling, and degradation of CL. This review will focus on recent developments on the role of CL in neurological disorders. Importantly, due to CL species in the brain being more unsaturated and diverse than in other tissues, this review will also identify areas where more research is needed to determine a complete picture of brain and spinal cord CL function so that effective therapeutics can be developed to restore the rates of CL synthesis and remodeling in neurological disorders.

Diacetylmorphine abuse is a major social problem that jeopardizes the world, and abuse can cause serious neurological disorders. Apoptosis plays an important role in neurological diseases. A previous study by our group found that the brain tissue of diacetylmorphine-addicted rats showed severe vacuole-like degeneration and increased apoptosis, but the exact mechanism has not yet been reported. We used TMT technology to sequence the diseased brain tissue of rats, and selected neurofilament light chain (NEFL) and neuritin (NRN1) as the focus of our research. We explore the possible roles and mechanisms played by both. Based on the construction of apoptotic cell model, we used overexpression/silencing lentiviral vectors to interfere with the expression of NEFL in PC12 cells, and the results suggested that NEFL could regulate NRN1 to affect the apoptosis level. To further understand the specific mechanism, we used transmission electron microscopy to observe the ultrastructure of apoptotic cells, and the results showed that compared with the control group, mitochondria in the model group showed obvious vacuolation as well as expansion, a significant increase in the accumulation of ROS, and a significant decrease in the mitochondrial membrane potential; after overexpression/silencing of NEFL, these changes were found to occur along with the alteration of NEFL expression. In summary, we conclude that diacetylmorphine induces neuronal apoptosis, and the specific mechanism is that NEFL regulates the NRN1-mediated mitochondrial pathway to promote apoptosis.

Ischemic stroke (IS) is one of the most common causes of death in the world. The lack of effective pharmacological treatments for IS was primarily due to a lack of understanding of its pathogenesis. Gα-Interacting vesicle-associated protein (GIV/Girdin) is a multi-modular signal transducer and guanine nucleotide exchange factor that controls important signaling downstream of multiple receptors. The purpose of this study was to investigate the role of GIV in IS. In the present study, we found that GIV is highly expressed in the central nervous system (CNS). GIV protein level was decreased, while GIV transcript level was increased in the middle cerebral artery occlusion reperfusion (MCAO/R) mice model. Additionally, GIV was insensitive lipopolysaccharide (LPS) exposure. Interestingly, we found that GIV overexpression dramatically restrained microglial activation, inflammatory response, and M1 polarization in BV-2 microglia induced by oxygen-glucose deprivation and reoxygenation (OGD/R). On the contrary, GIV knockdown had the opposite impact. Mechanistically, we found that GIV activated the Wnt/β-catenin signaling pathway by interacting with DVL2 (disheveled segment polarity protein 2). Notably, m⁶A demethylase fat mass and obesity-associated protein (FTO) decreased the N6-methyladenosine (m6A) modification-mediated increase of GIV expression and attenuated the inflammatory response in BV-2 stimulated by OGD/R. Taken together, our results demonstrate that GIV inhibited the inflammatory response via activating the Wnt/β-catenin signaling pathway which expression regulated in an FTO-mediated m⁶A modification in IS. These results broaden our understanding of the role of the FTO-GIV axis in IS development.

Rheumatoid arthritis (RA) is an autoimmune chronic inflammatory disease that imposes a heavy economic burden on patients and society. Bone and cartilage destruction is considered an important factor leading to RA, and inflammation, oxidative stress, and mitochondrial dysfunction are closely related to bone erosion and cartilage destruction in RA. Currently, there are limitations in the clinical treatment methods for RA, which urgently necessitates finding new effective treatments for patients. Nuclear transcription factor-κB (NF-κB) is a signaling transcription factor that is widely present in various cells. It plays an important role as a stress source in the cellular environment and regulates gene expression in processes such as immunity, inflammation, cell proliferation, and apoptosis. NF-κB has long been recognized as a pathogenic factor of RA, and its activation can exacerbate RA by promoting inflammation, oxidative stress, mitochondrial dysfunction, and bone destruction. Conversely, inhibiting the activity of the NF-κB pathway effectively inhibits these pathological processes, thereby alleviating RA. Therefore, NF-κB may be a potential therapeutic target for RA. This article describes the physiological structure of NF-κB and its important role in RA through the regulation of oxidative stress, inflammatory response, mitochondrial function, and bone destruction. Meanwhile, we also summarized the impact of NF-κB crosstalk with other signaling pathways on RA and the effect of related drugs or inhibitors targeting NF-κB on RA. The purpose of this article is to provide evidence for the role of NF-κB in RA and to emphasize its significant role in RA by elucidating the mechanisms, so as to provide a theoretical basis for targeting the NF-κB pathway as a treatment for RA.

N6-methyladenosine (m6A) is one of the most common post-transcriptional RNA modifications, which plays a critical role in various bioprocesses such as immunological processes, stress response, cell self-renewal, and proliferation. The abnormal expression of m6A-related proteins may occur in the central nervous system, affecting neurogenesis, synapse formation, brain development, learning and memory, etc. Accumulating evidence is emerging that dysregulation of m6A contributes to the initiation and progression of psychiatric disorders including depression. Until now, the specific pathogenesis of depression has not been comprehensively clarified, and further investigations are warranted. Stress, inflammation, neurogenesis, and synaptic plasticity have been implicated as possible pathophysiological mechanisms underlying depression, in which m6A is extensively involved. Considering the extensive connections between depression and neurofunction and the critical role of m6A in regulating neurological function, it has been increasingly proposed that m6A may have an important role in the pathogenesis of depression; however, the results and the specific molecular mechanisms of how m6A methylation is involved in major depressive disorder (MDD) were varied and not fully understood. In this review, we describe the underlying molecular mechanisms between m6A and depression from several aspects including inflammation, stress, neuroplasticity including neurogenesis, and brain structure, which contain the interactions of m6A with cytokines, the HPA axis, BDNF, and other biological molecules or mechanisms in detail. Finally, we summarized the perspectives for the improved understanding of the pathogenesis of depression and the development of more effective treatment approaches for this disorder.