Journal of Molecular Neuroscience最新文献

Developmental exposure to zinc/paraquat (Zn/PQ) increases susceptibility to dopaminergic neurodegeneration caused by adulthood exposure to Zn/PQ in rodents through augmented oxidative stress and inflammation. The current study delved into the consequences of developmental Zn/PQ exposure on the mechanism of neuronal apoptosis induced by Zn/PQ exposure in adult animals. Postnatal Zn/PQ exposure augmented the loss of dopaminergic neurons and mitochondrial reactive oxygen species production in animals that received Zn/PQ re-exposure at adult stage. A more pronounced decline was observed in mitochondrial complex I/III activity and membrane potential in animals that encountered both postnatal and adult stage exposures to Zn/PQ than in the animals exposed during adult stage only. Developmental Zn/PQ exposure noticeably enhanced apoptotic neuronal cell death in the animals who received adulthood re-exposure, as evident by the higher mitochondrial cytochrome c efflux into cytosol and reduction in procaspase-3 levels compared to the animals that encountered with Zn/PQ during adulthood alone. Whilst Zn exposure during adulthood pointed towards activation of Bax-mediated apoptotic cell death, exposure to PQ at adult stage suggested involvement of Bak-mediated apoptotic cell death irrespective of developmental exposure to PQ or Zn. The study indicated that early life exposure renders the dopaminergic neurons more susceptible to Zn/PQ-induced mitochondria-mediated apoptotic neuronal cell death following subsequent toxic insult in adult life. However, final apoptotic disposal pathway for dopaminergic neurons seems to be directed by the toxic insult encountered in adulthood.

Major depressive disorder (MDD) constitutes a substantial global health burden; however, the causal genes and cell-type-specific mechanisms underlying its pathogenesis remain incompletely understood. We conducted an integrative transcriptomic and proteomic Mendelian randomization (MR) study incorporating expression quantitative trait loci (eQTL) and protein quantitative trait loci (pQTL) datasets to prioritize genes associated with MDD. Candidate genes were further evaluated using neuron-specific single-cell eQTL analyses across multiple brain cell types, and brain imaging–derived phenotypes were assessed as exploratory structural mediators through two-step MR mediation analysis. Integrative eQTL-MR and pQTL-MR analyses identified 20 genes associated with MDD at both transcriptomic and proteomic levels. Notably, CKAP2 showed directionally discordant associations across molecular layers: genetically predicted CNS-related CKAP2 expression was inversely associated with MDD risk, whereas genetically predicted plasma CKAP2 protein levels showed an association in the opposite direction. Rather than establishing a unified causal mechanism across transcriptomic and proteomic layers, this discordance suggests that CKAP2-related genetic signals may differ across tissues, molecular layers, or instrument constructions. Single-cell eQTL analyses provided supportive evidence for a protective-direction association of CKAP2 expression in excitatory neurons (OR = 0.986, p = 0.007), inhibitory neurons (OR = 0.990, p = 0.007), and oligodendrocyte precursor cells (OR = 0.987, p = 0.009). Mediation analysis suggested that right thalamic ventral anterior nucleus volume may represent an exploratory imaging phenotype related to the CKAP2–MDD association, accounting for 17.0% of the total effect, although this finding requires independent replication. Sensitivity analyses provided no evidence of heterogeneity or horizontal pleiotropy, and reverse MR analyses showed no evidence of reverse causation, although these analyses were limited in statistical power. Collectively, these findings prioritize CKAP2 as a candidate gene with convergent but non-confirmatory genetic evidence for involvement in MDD, warranting further validation in independent causal and experimental frameworks.

Extracellular ATP is a central danger signal linking cellular stress to neuroinflammation, yet the mechanisms governing the transition from physiological purinergic signaling to pathological neuroimmune activation remain incompletely understood. In this review, we integrate current evidence into a conceptual framework describing how ATP-dependent purinergic signaling may contribute to the shift from adaptive neuron–glia communication to maladaptive glial crosstalk and inflammatory amplification. Under physiological conditions, controlled ATP turnover primarily engages lower-threshold purinergic pathways, including P2X4-mediated signaling that supports microglial surveillance, synaptic remodeling, and tissue homeostasis. In contrast, sustained extracellular ATP accumulation during injury, oxidative stress, or impaired ATP clearance preferentially recruits the low-affinity P2X7 receptor, triggering ionic dysregulation, Ca²⁺ influx, and redox-sensitive signaling pathways that promote NF-κB activation and NLRP3 inflammasome assembly. We further examine how receptor crosstalk, particularly with TLR4 and emerging redox regulatory mechanisms involving protein disulfide isomerase (PDI), may influence P2X7 signaling across different neuroinflammatory contexts. Finally, we discuss current evidence for therapeutic targeting of P2X7, highlighting translational challenges related to blood–brain barrier penetration, receptor occupancy, disease stage, and patient selection. By integrating recent advances in purinergic, redox, and neuroimmune signaling, this review provides a heuristic framework for understanding context-dependent P2X7 activation while distinguishing established mechanisms from emerging concepts that require further experimental validation.

Freezing of gait (FOG) is a disabling complication of Parkinson’s disease (PD), but peripheral associations remain poorly defined. C-terminal agrin fragment-22 (CAF22) is a circulating biomarker of neuromuscular junction degradation. We investigated whether baseline plasma CAF22 predicts the development of FOG in PD patients. In this prospective cohort study, 233 patients with idiopathic PD and no baseline FOG were followed for 24 months with assessments at 6-month intervals. Incident FOG was identified using the New Freezing of Gait Questionnaire. Cox proportional hazards models assessed associations between CAF22 and time to first FOG, adjusting for age, sex, disease duration, motor severity, gait speed, muscle strength, cognitive performance, and levodopa-equivalent daily dose. During follow-up, 55 participants (23.6%) developed incident FOG. Higher baseline plasma CAF22 was associated with an increased risk of FOG per standard deviation increase (HR 1.4, 95% CI 1.09–1.81). This association remained significant after multivariate adjustment (adjusted HR 1.37, 95% CI 1.03–1.82). Baseline CAF22 concentrations were higher in participants with greater motor severity and slower gait speed, but showed weaker associations with global cognitive performance. Faster gait speed was independently protective against FOG (HR 0.64, 95% CI 0.52–0.78). Kaplan–Meier analyses demonstrated progressively lower FOG-free survival across increasing CAF22 tertiles (log-rank p = 0.046). Elevated baseline plasma CAF22 independently predicts incident FOG in PD. CAF22 may reflect peripheral neuromuscular dysfunction and could serve as a biomarker of FOG risk.

Background: This study was designed to evaluate the genetic association of three specific intronic Single Nucleotide Polymorphisms (SNPs) within the Dopamine Receptor D2 (DRD2) gene—rs2005313, rs4274224, and rs4938019—with schizophrenia susceptibility in a Pakistani population. The primary objective was to identify population-specific biomarkers that could inform early intervention and personalized treatment strategies. Methods: Genotyping was conducted on a matched case-control cohort of 208 participants (104 cases; 104 controls) using High-Resolution Melting (HRM) PCR. Genetic associations were quantified using Odds Ratios (OR) and 95% Confidence Intervals (CI), representing the standard coefficient and its margin of error to ensure statistical precision. Functional annotation of the investigated polymorphisms was performed using GTEx, FORGEdb and RegulomeDB to assess regulatory potential and tissue-specific expression effects. Results: The research identified highly significant associations across multiple inheritance models, validating the technical robustness of the findings. The rs4938019 polymorphism emerged as the most potent genetic risk factor, particularly under the recessive model (OR: 9.60; 95% CI: 3.92–23.52; p < 0.0001), where the rare GG genotype was found in 44% of cases compared to only 7.2% of controls. Conversely, rs4274224 demonstrated a significant protective effect, with a co-dominant OR of 0.23 (95% CI: 0.09–0.59; p = 0.0022), suggesting that the T allele confers genetic resilience. Furthermore, among the investigated DRD2 variants, rs2005313 demonstrated significance primarily under the over-dominant inheritance model, whereas rs4938019 exhibited the strongest association under the recessive model (OR: 2.13; 95% CI: 1.15–3.94; p = 0.014). All variants in the control group maintained Hardy-Weinberg Equilibrium (p > 0.05), confirming the absence of population bias. Functional annotation revealed that rs4274224 showed the strongest direct regulatory evidence for DRD2 (FORGEdb score: 6; RegulomeDB Rank 1f), while rs4938019 demonstrated the highest overall regulatory potential (FORGEdb score: 9), with rs2005313 exhibiting substantial regulatory evidence (FORGEdb score: 7) supported by extensive GTEx cis-eQTLs across multiple tissues including brain regions. Conclusion: These findings establish DRD2 intronic polymorphisms as critical determinants of schizophrenia risk. The high-risk rs4938019 GG genotype provides a clear translational biomarker for rapid genetic screening, potentially improving clinical outcomes through genotype-guided therapeutic interventions.

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Aging is characterized by increased reactive oxygen species (ROS) and leads to mitochondrial dysfunction. This age-related decline in mitochondrial function is a major factor in the development of neurodegenerative diseases. Mitochondrial permeability transition pore (PTP) is a multi-protein complex that forms a non-specific channel across the inner mitochondrial membrane, and its opening is tightly linked to mitochondrial function and cell death. Dysregulation of PTP opening is now recognized as a central pathogenic mechanism in both normal aging and age-associated neurodegenerative diseases. This review integrates current understanding of mitochondrial permeability transition with emerging evidence implicating three novel regulatory components: F-ATP synthase inhibitory factor 1 (IF1), subunit j of F-ATP synthase, and mitochondrial carrier homolog 2 (MTCH2), expanding the therapeutic landscape for treating aging and neurodegeneration through targeting the PTP.

The neurodegenerative illness Alzheimer’s disease (AD) causes cognitive decline. The production of oxidative stress in neurons is thought to play a role in the emergence of AD. The antioxidants, including kaempferol, reduce the course of AD; however, their use is limited by poor bioavailability. Kaempferol-conjugated manganese oxide nanocomposites (KMF@PEG-MnO2 NCs) exhibit enhanced protective effects against AD compared to free kaempferol. In this study, the potential of KMF@PEG-MnO₂ NCs as an anti-Alzheimer’s disease (AD) agent was explored through in silico and experimental approaches. The effective preparation of KMF@PEG-MnO₂ NCs was validated by FT-IR, XRD, DLS, and SEM-EDX characterization techniques. The influence of KMF@PEG-MnO₂ NCs on antioxidant capacity using the DPPH assay, reactive oxygen species (ROS) quantification with the SH-SY5Y cell line, and determining the amyloid β disaggregation was determined. Additionally, blood-brain barrier permeability was assessed with brain endothelial cells, and an anticholinesterase study was performed to explore its potential for treating Alzheimer’s disease. Surface characterization revealed a spherical shape of the nanoparticle. DPPH and FR assay showed a substantial rise in antioxidant defence for KMF@PEG-MnO₂ NCs compared to KMF. Anti-aggregation studies demonstrated the nanoparticle’s ability to inhibit Aβ fibrils. Additionally, the BBB permeability assay indicated that the nanoparticle can permeate the BBB. Furthermore, in vivo studies demonstrated that KMF@PEG-MnO₂ NCs protected against cognitive and synaptic deficits in AlCl₃-induced AD rats (AlCl₃-AD). KMF@PEG-MnO₂ NCs significantly reduced AChE activity. Furthermore, it markedly reduced the brain’s levels of nitric oxide (NO) while increasing the function of superoxide dismutase (SOD) and catalase (CAT) activities. Overall, the findings suggest that KMF@PEG-MnO₂ NCs may serve as a promising therapeutic candidate for AD management.

Autism Spectrum Disorder (ASD) is associated with neuroinflammation and oxidative stress that disrupt neurodevelopmental processes. Resveratrol (RSV) is a polyphenol with antioxidant and anti-inflammatory properties, but its poor bioavailability limits therapeutic use. This study investigated whether PEGylated liposomes encapsulating RSV (LipRSV) could modulate oxidative and behavioral alterations in a valproic acid (VPA)-induced rat model of ASD. PEGylated LipRSV were synthesized, characterized as hemocompatible, and administered to offspring from postnatal day (PND) 6 to 27. Behavioral tests included developmental milestones, olfactory discrimination, negative geotaxis, open field, and three-chamber social interaction. Oxidative stress markers and neurotrophins (BDNF, NGF) were quantified in the following brain regions: hippocampus, hypothalamus, striatum, cerebellum, frontal and posterior cortex. LipRSV exerted limited and region-dependent redox effects, reducing ROS levels only in the hippocampus, cerebellum, and posterior cortex, while failing to improve behavioral outcomes and being associated with unfavorable neurochemical alterations, including reduced BDNF and NGF levels. Importantly, LipRSV also induced behavioral deficits, redox imbalance, and neurochemical alterations in control animals, indicating treatment-related effects in the absence of VPA exposure. LipRSV modulated oxidative stress in a region-dependent manner without improving behavioral deficits in the VPA model and was associated with reduced BDNF and NGF levels. This study provides evidence that modulation of oxidative stress alone is insufficient to rescue behavioral phenotypes in the VPA model of ASD. These findings highlight the partial neurochemical efficacy and translational limitations of this formulation, suggesting the need for optimized nanocarrier design and dosing strategies in ASD pharmacotherapy.

The peroxisome proliferator-activated receptor delta (PPARδ) is a nuclear receptor highly expressed in vasculature and serves a central role in coordinating vascular and metabolic homeostasis across multiple physiological systems. Recent studies have highlighted PPARδ’s remarkable ability to regulate endothelial fatty acid oxidation, enhance metabolic flexibility, and modulate angiogenic responses critical for vascular adaptation and repair. Beyond its metabolic functions, PPARδ orchestrates multiple protective pathways that preserve cerebrovascular homeostasis, including endothelial repair, maintenance of blood-brain barrier integrity, mitochondrial biogenesis, and stability of the neurovascular unit, collectively enhancing endothelial resilience to stress. Dysregulation of PPARδ signaling has been implicated in various vascular and neurodegenerative disease states, underscoring its clinical relevance. In this literature review, we synthesize current findings on PPARδ-mediated signaling pathways and evaluate its potential as a promising therapeutic target. We further explore mechanistic roles across pathological contexts, as well as discuss emerging translational strategies aimed at harnessing PPARδ modulation for vascular and neuroprotective therapies.

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