Journal of Molecular Neuroscience最新文献

Facioscapulohumeral muscular dystrophy(FSHD) is a genetic and heterogeneous neuromuscular disorder primarily driven by DUX4 derepression. The marked clinical variability observed among affected individuals suggests the presence of additional genetic modifiers, however underlying factors remain largely unclear. Investigating coincidental hereditary conditions within families may provide critical insights into such modifying mechanisms. We investigated a multigenerational family exhibiting the co-occurrence of FSHD and hereditary macrothrombocytopenia. Detailed neurological and hematological evaluations were performed across family members. Trio whole-exome sequencing(WES) was performed in selected individuals, followed by DNA sequencing and segregation analysis of identified genes. In silico structural analyses were performed for candidate variants. Candidate variants were additionally screened in an independent cohort with next generation sequencing. Clinical severity was assessed using the Clinical severity score(CSS), FSHD clinical score, and age-corrected CSS(ACSS). Trio-WES analysis identified a pathogenic frameshift mutation(c.1848delT) in GP1BA gene, responsible for macrothrombocytopenia. Among candidate variants located near GP1BA, a missense variant in MYH2(c.5045G > A) was prioritized due to its known association with myopathy and its involvement in DUX4-related pathways. Segregation analysis revealed that GP1BA mutations were present in five of nine FSHD-affected individuals, four of whom also harboured the MYH2 variant. Neither mutation was detected in unaffected family members. Individuals carrying the MYH2 variant consistently exhibited higher ACSS values compared to family members who did not carry the variant. Screening of MYH2 c.5045G > A (p.Arg1682His) and GP1BA c.1848delT variants in an independent cohort of 30 FSHD1 patients revealed no variant carriers, with all individuals exhibiting a wild-type genotype. Network analysis focusing on the interaction landscape between the FSHD key protein DUX4 and MYH2, using the Integrated Interactions Database(IID), revealed ACTN1 as a connecting node linking these pathways. Our findings suggest that rare MYH2 variants may act as a genetic modifier influencing the clinical severity in FSHD, which has not been previously reported. This study highlights the value of investigating co-occurring hereditary conditions to uncover novel molecular contributors to disease heterogeneity in FSHD. The potential role of MYH2 and its rare variants as genetic modifiers should be further validated in larger cohorts and functional studies.

Graphical Abstract

Human umbilical cord mesenchymal stem cells (hUCMSCs) have shown promise for treating ischemic stroke (IS) by promoting neural repair. The Notch signaling pathway is known to regulate neural stem cell (NSC) proliferation and differentiation, but its role in hUCMSC-mediated neuroprotection remains unclear. This study aimed to evaluate the therapeutic effects of hUMSCs in a mouse model of middle cerebral artery occlusion (MCAO) and investigate the involvement of the Notch pathway. Fifth generation of hUCMSCs were characterized by flow cytometry. In vitro, hUCMSCs were induced to differentiate with or without DAPT (a Notch inhibitor) or Jagged1 (a Notch agonist), and neural differentiation was assessed by Nestin and MAP2 expression. In vivo, MCAO mice received hUCMSC transplantation, and NSC proliferation, differentiation, and neural repair were evaluated using BrdU/Nestin immunofluorescence, qRT-PCR, Western blot, mNSS scoring, TTC, Nissl, and TUNEL assays. HUCMSCs displayed typical mesenchymal markers (CD90, CD44, CD105, and CD73) and low expression of hematopoietic markers. In vitro, DAPT enhanced hUCMSC differentiation into neuron-like cells, while JAG1 reversed this effect, confirming the mechanistic role of Notch signaling. In MCAO mice, hUCMSC transplantation promoted NSC proliferation and differentiation in the SVZ, reduced infarct volume and water content, increased Nissl-positive neurons, decreased apoptotic cells, and lowered mNSS scores. Inhibition of Notch signaling further augmented these therapeutic effects. HUCMSCs promote neural differentiation and neuroprotection in ischemic brains, at least in part by modulating the Notch signaling pathway. These findings highlight hUCMSCs as a promising therapeutic strategy for IS.

Focal demyelination refers to localized loss of myelin sheath that surrounds the nerve fibers. It impairs the efficient transmission of nerve impulses results in neurological symptoms. Here, our goal is to investigate the differential and combined effects of lysolecithin (LPC) and lipopolysaccharides (LPS) on brain and spinal cord demyelinating process. To confirm the pattern of demyelination, behavioural analysis was performed. Further, brain and spinal cord samples were collected at Day-post injection-1, 3, 7, and 28. The loss of axonal structures and neuronal bodies were assessed using Luxol fast blue and Nissl staining respectively. Immunofluorescence studies were done to examine demyelination and its impact on endothelial activation, astrogliosis, and activated microglia. Our data revealed that the combination group exhibited remarkable demyelination compared to the LPC and LPS groups alone. Additionally, endothelial activation, astrogliosis, and activated microglia were more pronounced in the combination group. Moreover, we found much of these effects were most pronounced in the spinal cord compared to corpus callosum, suggesting the presence of compensatory mechanisms and a unique brain microenvironment. This study is the first to demonstrate the synergistic effects of LPC and LPS toxins compared to their individual effects in both the brain and spinal cord.

While anti-amyloid immunotherapy has shown clinical benefit, amyloid-related imaging abnormalities (ARIA), comprising vasogenic edema (ARIA-E) and microhemorrhages (ARIA-H), represent the principal safety limitation. This paper presents a theoretical construct not yet based on empirical data. As a theoretical construct, we systematically synthesize current published findings on ARIA pathophysiology, plasma biomarker biology (glial fibrillary acidic protein [GFAP], amyloid-beta [Aβ] 42/40 ratio, neurofilament light chain [NfL], and phosphorylated tau [p-tau217]), and clinical trial outcomes. We propose that ARIA is fundamentally a kinetic—not static—pathological event, driven by the velocity of immune-mediated amyloid clearance. The Neuro-Pharmacological Kinetic Stress Test (NPKST) measures plasma biomarker velocity (rate of change per unit time) at Days 3–4 and 7 following the first therapeutic dose. A rapid spike in plasma GFAP velocity (ΔpGFAP/Δt), a precipitous decline in Aβ42/40 ratio velocity, and early NfL elevation constitute early biochemical signatures of individuals at high risk for clinically significant ARIA before macroscopic MRI changes are detectable. The Biomarker Velocity Composite Index (BVCI) stratifies patients into Low, Intermediate, and High Velocity tiers, each linked to specific dosing modification protocols. The cardiac stress test analogy provides the conceptual scaffold: the first therapeutic dose serves as the ‘pharmacological stress,’ and the BVCI captures the individual’s dynamic neuro-immune-vascular response phenotype. This proposed theoretical framework, if validated through future pilot studies and the KINETIC-ARIA trial, would shift ARIA prevention from reactive MRI surveillance to proactive biomarker-guided risk management. Long-term monitoring of potential ARIA effects is warranted.

Parkinson’s disease (PD) and Alzheimer’s disease (AD) are both neurodegenerative disorders sharing overlapping pathological mechanisms. Several studies suggest that AD biomarkers may have diagnostic and predictive value in PD, but causal evidence remains insufficient. This study aimed to explore the association between AD-related biomarkers and PD. Bidirectional two-sample Mendelian randomization (MR) was performed using GWAS summary statistics of AD-related biomarkers and PD to assess causal relationships. Subsequently, single-nucleus RNA sequencing (snRNA-seq) of postmortem midbrain tissues was employed to examine the expression of AD biomarkers in PD patients and to explore underlying cellular signaling pathways. Forward MR revealed a significant causal association between PD and decreased CSF p-tau levels. PD progression showed significant causal associations with decreased CSF Aβ42 and increased CSF total tau. Reverse MR indicated that elevated CSF total tau may increase PD risk. SnRNA-seq analysis demonstrated that MAPT (encoding tau) was predominantly expressed in dopaminergic neurons, with differentially expressed genes enriched in PD- and neurodegeneration-related pathways. Our findings provide preliminary, hypothesis-generating evidence at the genetic level suggesting potential associations between CSF tau, Aβ42, and PD or its progression. Bidirectional MR analyses suggest that CSF total tau may be associated with increased PD risk, while exploratory snRNA-seq analysis indicates that MAPT is predominantly expressed in dopaminergic neurons with enrichment in PD-related pathways. Given the limited number of instrumental variables for several exposures, the small snRNA-seq cohort, and the absence of protein-level validation, these findings should be interpreted with caution. Large-scale prospective clinical studies with protein-level biomarker assessment, tau-PET imaging, and independent multi-cohort transcriptomic validation are warranted before CSF total tau can be considered a candidate biomarker for PD progression.

The mechanisms underlying seizure-induced cortical injury in status epilepticus-related experimental epilepsy remain incompletely understood, and upstream regulators of inflammasome activation require further clarification. By combining bioinformatics screening with in vivo validation, we examined whether the MTRNR2L1/MTRNR2L10 axis is associated with NLRP3 inflammasome-related signaling in the cerebral cortex of rats subjected to status epilepticus, with the goal of identifying candidate regulators of seizure-induced cortical injury. The GSE134697 dataset was obtained from GEO. Differentially expressed genes (DEGs) were screened using |log2FC|>4 and adjusted P < 0.05. GO/KEGG enrichment analyses, together with a STRING-based protein–protein interaction (PPI) network, prioritized MTRNR2L1/MTRNR2L10 as candidate molecules annotated to the “regulation of signal transduction” pathway for subsequent in vivo validation. Ninety SPF SD rats (10 per group) were used: a basic model module (normal, sham, and EP model) and a target-intervention module (six groups: negative control, overexpression, and knockdown for MTRNR2L1/MTRNR2L10). Behavioral scoring, histopathology, Western blotting, co-immunoprecipitation, and ELISA were performed. Fifty-one DEGs were identified. Among them, only MTRNR2L1/MTRNR2L10 mapped to signal-transduction regulation associated with EP, and their cortical expression in EP rats fell to < 30% of control. Upregulating this axis lowered Racine seizure scores and neurological deficit scores, was associated with reduced NLRP3 inflammasome-related marker expression, mitigated the loss of BBB-related tight-junction protein markers, and reduced cortical neuronal apoptosis. In contrast, silencing either target exacerbated these changes, and co-immunoprecipitation suggested that the two molecules were associated within the same protein complex. The MTRNR2L1/MTRNR2L10 axis may act as a candidate protective regulator in status epilepticus-related experimental epilepsy, in association with reduced NLRP3 inflammasome-related signaling. These findings support further mechanistic evaluation of MTRNR2L1/MTRNR2L10 in seizure-induced cortical injury, but do not establish these molecules as therapeutic targets for drug-resistant epilepsy.

Neuronal ceroid lipofuscinosis (NCL) is a group of progressive neurodegenerative disorders affecting the brain and retina. This study descriptively characterizes Magnetic Resonance Imaging (MRI) and Proton Magnetic Resonance Spectroscopy (^1H MRS) features across NCL subtypes in 16 patients and preliminarily explores potential associations with clinical severity and genetic findings. Due to the small sample size, no definitive genotype–phenotype correlations could be established; rather, we report observed imaging patterns as hypothesis-generating observations. MRI demonstrated patterns such as thalamic T2-weighted hypointensity and periventricular white matter signal abnormalities, which may reflect disease burden and progression. ^1H MRS, performed in a subset of patients, showed reduced N-Acetyl Aspartate and variable choline peaks. Notably, preliminary subtype-specific metabolic trends were observed across the four subtypes in which MRS was performed, suggesting the potential for metabolite profiling to aid in diagnosis and subtype differentiation. However, these findings are merely exploratory and require validation in larger cohorts. These preliminary findings suggest a complementary role for advanced neuroimaging alongside molecular testing in the early diagnosis and evaluation of NCL, though larger prospective studies are needed to validate these observations.

RAPGEF6 is a member of the guanine nucleotide exchange factor (GEF) subfamily that acts on Rap small GTPases and contains a Ras/Rap-associating domain. Although deficiency of this gene has previously been linked to schizophrenia, no MIM phenotype entry currently associates RAPGEF6 with a defined clinical condition. In this study, trio-based whole-exome sequencing (WES) was performed in an individual presenting with psychiatric disorders and mild intellectual disability. WES revealed a de novo frameshift variant, c.272dup (p.Pro92Serfs*6), in the RAPGEF6 gene (NM_016340.6). This variant was classified as likely pathogenic according to ACMG criteria. Nonetheless, the contribution of additional genetic factors not detected by WES cannot be excluded. According to developmental transcriptomic data from the BrainSpan database, RAPGEF6 is expressed in the human brain across the entire lifespan and participates in neuron projection development, Rap-protein signal transduction, and regulation of GTPase activity. Structural variation data from DECIPHER further indicate that copy-number variants involving RAPGEF6 are primarily associated with intellectual disability and micrognathia. In addition, DECIPHER shows that RAPGEF6 is highly intolerant to loss-of-function (LoF) variants. Both NMD-Esc predictor and Mutation Taster suggest that the identified frameshift mutation is likely to trigger nonsense-mediated decay (NMD) of the RAPGEF6 transcript, resulting in loss of protein production. In addition, RAPGEF6 expression progressively increased during retinoic acid-induced neuronal differentiation of SK-N-BE neuroblastoma cells, supporting a potential role of this gene in neuronal maturation processes. Together, these data support a contributory role of RAPGEF6 haploinsufficiency in neurodevelopmental and psychiatric phenotypes, reinforcing its emerging relevance in neuropsychiatric disorders.

Acrylamide (ACR) is a heat-generated carcinogen, one of the most common toxins, with various effects on the biological system, including oxidative stress and related disorders. Umbelliferone (UMB) is a naturally occurring coumarin derivative that is present in edible fruits, known as an antioxidant, and reported for many other therapeutic effects. In the current study, UMB was evaluated for neuro- and hepatoprotective activity against oxidative stress toxicity induced by a 40 mg/kg daily dose of ACR in a mouse model over 15 days. Also, UMB was used as a ligand for the first time to predict its affinity for the most important proteins involved in neuronal failure. The UMB administration significantly improves liver enzyme elevations, alanine transaminase (ALT) and aspartate transaminase (AST), following ACR injection. Also, UMB treatment reduced elevated total protein (TP) and albumin (ALB) serum levels. In addition, lipid peroxidation levels were significantly reduced by UMB (expressed as malondialdehyde MDA levels), and the levels of total non-enzymatic antioxidant capacity (TAC) were increased in brain tissue homogenate in comparison with brain injury in the ACR group. Furthermore, UMB downregulated the expression of tumor necrosis factor-alpha (TNF-α), an inflammatory marker and caspase-3, an apoptotic marker, while upregulating heme oxygenase-1 (HO-1), an antioxidant enzyme, in both liver and brain tissues. Molecular docking analysis revealed that the compound could form H-bonds and hydrophobic interactions with the target receptors. Results of this study conclude that UMB may be considered a potential pharmaceutical agent to ameliorate ACR-induced toxicity in the liver and brain, due to its anti-inflammatory, antioxidant, and antiapoptotic mechanisms, as well as its moderate affinity for neuronal disease-targeted proteins.

This review critically evaluates exercise-induced myokines as neuroprotective agents against Alzheimer’s disease (AD) and is structured around three thematic sections: (1) mechanistic foundations of myokine neuroprotection, (2) translational barriers to therapeutic development, and (3) a strategic framework for future research. Epidemiological studies associate physical exercise with reduced AD risk (30–45%), yet mechanisms remain incompletely resolved. Preclinical studies demonstrate that exercise-induced myokines (Irisin, BDNF, Cathepsin B) modulate AD pathology by: (1) attenuating amyloid-beta (Aβ)/tau accumulation, (2) suppressing neuroinflammation, and (3) enhancing synaptic plasticity. However, human exercise interventions show conflicting results influenced by APOE genotype, age, and exercise modality. Associative human data suggest that Interleukin-6 (IL-6) exemplifies pleiotropy—affording neuroprotective effects in acute contexts but potentially detrimental effects in states of chronic inflammation. Therapeutic hurdles include blood-brain barrier (BBB) penetration, pleiotropic risks, and patient heterogeneity. Emerging concepts such as combinatorial approaches (nanocarriers, exercise mimetics) and biomarker-driven trials are proposed as hypothetical future strategies; however, these remain unvalidated and require substantial preclinical development before implemented in clinical care. This narrative review is structured around three thematic sections: mechanistic foundations of myokine neuroprotection, translational barriers to therapeutic development, and a strategic framework for future research. The muscle-brain axis represents a compelling but complex therapeutic target. Based on current preclinical and correlational human evidence, future research should prioritize mechanistic rigor, standardized biomarker validation, and clinically viable delivery strategies. Notably, several approaches discussed herein—including nanocarrier delivery systems, exercise mimetics, and combinatorial myokine cocktails—remain speculative and are presented as future research directions rather than established therapeutic interventions.