Frontiers in Molecular Neuroscience最新文献

Background: Spinal Cord Injury (SCI) is a severe central nervous system disorder that initiates inflammatory reactions, exacerbating tissue damage and impeding neuronal repair. Macrophage polarization plays a critical role in this pathological process: it significantly regulates inflammation resolution and tissue regeneration, rendering its modulation a key strategy for SCI repair. Omaveloxolone (Omav), a novel Nrf2 activator, has demonstrated potential in regulating inflammatory responses, suggesting it may serve as a promising candidate for SCI intervention.

Methods: To evaluate the efficacy and underlying mechanism of Omav in SCI repair, a spinal cord contusion model was established in animal subjects. Additionally, an in vitro lipopolysaccharide (LPS)-induced macrophage polarization model was constructed to further validate Omav's effects on macrophage phenotypes. RNA sequencing (RNA-seq) was employed to elucidate the molecular pathways through which Omav modulates post-SCI pathophysiology.

Results: In vivo experiments revealed that Omav effectively restored motor function in SCI-induced animals. RNA-seq analysis further demonstrated that Omav reshaped inflammatory cascades following SCI, with a significant impact on macrophage polarization dynamics. Specifically, Omav promoted the formation of an M2-dominant macrophage landscape (a phenotype associated with anti-inflammation and tissue repair) while reducing the pro-inflammatory M1 macrophage phenotype. These findings were corroborated by in vitro studies, which confirmed that Omav directly facilitated M2-type macrophage polarization.

Conclusion: Our results collectively confirm the efficacy of Omav in repairing spinal cord injury by targeting macrophage polarization and regulating inflammatory responses. This study not only highlights the therapeutic potential of Omav for SCI but also provides a novel pharmacological strategy for SCI treatment.

FK506-binding protein 51 (FKBP51) is a pivotal molecular chaperone and scaffolding protein that integrates and modulates multiple signaling pathways-including those involving HSP90, the glucocorticoid receptor, AKT, and NF-κB-through its FK1, FK2, and TPR domains, thereby playing a central role in the maintenance of central nervous system (CNS) homeostasis. This review systematically elaborates on the pathological mechanisms and therapeutic potential of FKBP51 in a variety of CNS disorders. In neurodegenerative diseases, FKBP51 promotes aberrant aggregation of Tau protein via the HSP90 complex, exacerbating the pathological progression of Alzheimer's disease; in Parkinson's disease, it influences neuronal survival through interaction with the PINK1/AKT signaling pathway; while in Huntington's disease, it impairs the clearance of mutant huntingtin (mHTT) protein. In models of ischemic stroke, upregulation of FKBP51 enhances autophagy and inflammatory responses through pathways such as AKT/FoxO3, thereby amplifying brain injury. In glioma, FKBP51 exhibits a context-dependent dual role: it may exert tumor-suppressive effects by inhibiting Akt, while its splice variant FKBP51s can regulate PD-L1 expression, promoting tumor immune evasion and therapy resistance. Emerging highly selective small-molecule inhibitors, gene-editing technologies, and novel applications of conventional drugs targeting FKBP51 have demonstrated significant interventional potential in preclinical studies. In summary, FKBP51 constitutes a pleiotropic signaling node, positioning it as a prime therapeutic target for a broad spectrum of CNS disorders.

Within the significant worldwide causes of mortality and morbidity are congenital heart diseases. Congenital cardiomyopathies include conditions in which early diagnosis and care can improve survival and health. In general, the first diagnostic tool is clinician suspicion followed by appropriate imaging, classically an echocardiogram. Cardiomyopathies have high rates of clinically detectable genetic causes. In view of this, prompt genetic testing is highly recommended for patients with cardiomyopathy. Genetic diagnosis, that is relevant to both the patient and family members, can help guide the selection of appropriate therapies and provide valuable information about the presence of comorbidities in other organ systems. Congenital Disorders of Glycosylation (CDG) are a growing group of inherited multisystem disorders characterized by defects in the glycosylation of proteins and lipids. Hypertrophic / dilated cardiomyopathy and neuromuscular abnormalities are recurrent manifestations of glycosylation defects. Mutations within the gene encoding the human transmembrane protein 165 (HsTMEM165), that belong to uncharacterized protein family 0016 (UPF0016), have been associated with cases of CDG. Recent progress in basic and clinical research related to TMEM165, focusing on the pathogenicity of HsTMEM165 variants, are reviewed. Highlights include the critical role of amino acid replacement for maintaining the structural and functional integrity of TMEM165 and their known associations with phenotypes of CDG patients. Future directions in this rapidly evolving area of research are proposed, to recognize the potential involvement of HsTMEM165 in congenital cardiomyopathies.

Introduction: Alzheimer's disease (AD) is neurodegenerative disorder characterized by chronic inflammation in the brain. Chitinase-3-like 1 (CHI3L1), a secreted glycoprotein that is upregulated in a variety of diseases with chronic inflammation, represents a promising target for AD. Here, we studied the inhibitory effect of a novel CHI3L1 monoclonal antibody (H1) on memory impairment and neuroinflammation in Tg2576 transgenic mice.

Methods and results: H1 was shown to cross the blood-brain barrier selectively, as confirmed by fluorescence imaging. Tg2576 mice were administered H1 (2 mg/kg, i.v., weekly for 1 month), and cognitive functions were assessed through behavioral tests. H1 treatment alleviated memory impairment and reduced amyloid deposition and neuroinflammation both in Tg2576 mice and Aβ-induced BV-2 microglial cells. Mechanistically, H1 inhibited the ERK and NF-κB signaling pathways and suppressed M1 microglial marker expression. Global proteomic analysis and gene expression profiling in BV-2 cells and Tg2576 mouse brains revealed a strong association between CHI3L1 and HAX1 expression. H1 therapy significantly reduced HAX1 levels in both in vivo and in vitro models. Moreover, HAX1 induction by Aβ or CHI3L1 was blocked by an NF-κB inhibitor.

Discussion: These findings suggest that CHI3L1 monoclonal antibody therapy may attenuate cognitive decline in AD by modulating neuroinflamma.

Adolescence is a critical late phase of the neurodevelopment, characterized by marked brain plasticity and increased vulnerability to environmental challenges such as alcohol exposure. This study examined the impact of binge-like alcohol exposure in male Swiss Webster mice, focusing on oxidative damage, epigenetic and transcriptional alterations in key brain regions, such as the prefrontal cortex, cerebellum, striatum and hippocampus. Our results demonstrated that acute alcohol exposure during adolescence induces oxidative damage with significant alterations in global DNA methylation and gene expression involved in epigenetic regulation with distinct temporal and anatomical profiles. In the prefrontal cortex binge-like alcohol exposure exhibited persistent upregulation of genes associated with DNA methylation and histone deacetylation, consistent with prolonged transcriptional silencing that may impair executive functions and decision-making. The hippocampus appeared particularly sensitive, exhibiting marked decreases in DNA methylation and gene expression changes associated with an open chromatin state leading potentially linked to cognitive impairments in memory and learning impairments in memory and learning. In the striatum, binge-like alcohol exposure induced active DNA demethylation and transient modulation of histone methyltransferases, reflecting a dynamic compensatory response to alcohol-induced transcriptional repression, with implications for reward processing and impulse control. Similarly the cerebellum displayed a biphasic transcriptional pattern suggesting adaptive or homeostatic mechanisms aimed at maintaining cellular and synaptic balance. Collectively, these findings, accompanied by alterations in behavioral tests, highlight the regional specificity of epigenetic remodeling induced by excessive alcohol exposure during adolescence and offer new insights into the molecular mechanisms underlying increased neurodevelopmental vulnerability during this period.

Ubiquilin-2 (UBQLN2) is a ubiquitin (Ub)-binding shuttle protein that is mutated in X-linked forms of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). ALS/FTD-linked mutations in UBQLN2 disrupt its conformation, increasing its tendency to form cytoplasmic aggregates that may disrupt cellular regulation through loss-of-function (LOF) and gain-of-function (GOF) effects. Here, we performed quantitative mass spectrometry (MS)-based interactome analysis of wild-type (UBQLN2^WT) and ALS-mutant UBQLN2 (UBQLN2^ALS) proteins using inducible pluripotent stem cells (iPSCs) and induced motor neurons (iMNs). Proteins showing enhanced association with UBQLN2^ALS proteins included PEG10, a known degradation target of UBQLN2, and BAG6, a chaperone involved in the triage of mislocalized proteins (MLPs). BAG6 knockdown inhibited the solubility recovery of both UBQLN2^WT and UBQLN2^ALS proteins following heat stress (HS), suggesting it functions as a UBQLN2 holdase. In addition, knockdown of BAG6 or knockout of UBQLN2 led to PEG10 accumulation, implicating both in PEG10 turnover; however, neither BAG6 nor UBQLN2 was required for PEG10 degradation in response to HS. A highly aggregation-prone UBQLN2^4XALS mutant harboring four different ALS-associated mutations showed increased PEG10 binding and modestly delayed PEG10 turnover while PEG10 degradation was not significantly different between UBQLN2^WT and iPSCs expressing a UBQLN2^P497H clinical mutant. The combined findings implicate BAG6 as a UBQLN2 holdase and identify a suite of proteins whose altered binding may contribute to pathologic changes in UBQLN2-associated ALS/FTD.

Amyotrophic lateral sclerosis (ALS) is characterized by the progressive loss of upper and lower motor neurones, leading to muscle wasting, paralysis and respiratory failure. Pathological cytoplasmic aggregation of the RNA-binding protein transactive response DNA-binding protein 43 (TDP-43) protein occurs in neural tissues in ~97% of all ALS cases, and is also observed in skeletal muscle. Cytoplasmic aggregation of TDP-43 is believed to contribute to ALS pathogenesis; however, its precise mechanistic role/s continues to elude the field. This mini review explores the potential role and regulation of two TDP-43-associated RNA-protein assemblies, stress granules (SGs) and myogranules (MGs). We review the current understanding of SG and MG formation and their potential role in ALS-related neurodegeneration and muscle pathology. We also highlight limitations and strengths and suggest future directions for research.

Introduction: Neuropathic pain (NP) is a kind of common and intractable chronic pain. Hydrogen (H₂)-rich water exhibited protective effects in NP by intrathecal injection, drinking, and intraperitoneal injection. The nanobubble H2-dissolved water (NHW) is a solution that contains H₂ bubbles and H₂ in lysis state. Therefore, this study aimed to observe the effects of ultrasound-guided local injection with NHW in the model of NP, and try to find its possible mechanism.

Methods: The rat sciatic nerve was ligated to establish chronic constriction injury (CCI)-induced NP model. The CCI rats received NHW at low or high concentrations 1 or 3 times (n = 6). During the experiment, the paw withdrawal thresholds (PWT) and paw withdrawal latency (PWL) were detected. At 14 days after CCI, the organizational structure of nerve, inflammatory response, and oxidative stress damage were measured. Additionally, the Nrf2/HO-1 and sulfiredoxin-1 were also detected by western blotting and RT-PCR.

Results: Compared with low concentration, in the high concentration group, the PWT and PWL were attenuated on Day 1, 3, 5, 7, and 14 after CCI (p < 0.05). On Day 14, nerve injury, inflammatory response, and oxidative stress injury were relieved significantly in high concentration than at low concentration, and the effect was greater at multiple doses (3 times) at high concentrations (p < 0.05), as were the increase in the protein and mRNA levels of Nrf2/HO-1 and sulfiredoxin-1.

Conclusion: Ultrasound-guided early local injection of NHW attenuated sciatic nerve injury, alleviated mechanical allodynia and thermal hyperalgesia and inhibited inflammation and oxidative stress damage via the Nrf2/HO-1-sulfiredoxin1 pathway in a rat model of CCI.