Journal of Molecular Neuroscience最新文献

Oxidative stress (OS) is critically implicated in the onset and progression of neurodegenerative diseases (NDDs), yet its genetic determinants remain insufficiently elucidated. This study aims to delineate the putative causal relationships between OS-related genes (OSRGs) and NDDs, along with the potential regulatory and pathogenic mechanisms. Summary-data-based Mendelian randomization (SMR) was conducted to explore the putative causal associations of 936 OSRGs with NDDs, integrating genome-wide association studies (GWAS) data and expression quantitative trait loci (eQTL) data, using a multi-cohort design with blood eQTLs for discovery and replication, followed by brain eQTL validation. Subsequently, colocalization analysis was used to verify putative causal inferences in SMR. In addition, DNA methylation regulation and pathway enrichment analyses were applied to explore potential regulatory and pathogenic mechanisms. Genetically predicted levels of 15 genes were found to be significantly associated with the risk of NDDs. Higher genetically predicted expression of ACE and TP53INP1 was associated with decreased Alzheimer’s disease risk, whereas higher TSFM expression was associated with increased multiple sclerosis risk; these associations were consistently supported by replication cohort and brain eQTL validation for ACE and TSFM, while TP53INP1 showed brain-level consistency without replication. Among 15 genes, the expression levels of ACE, TP53INP1, and other 5 genes were regulated by DNA methylation. Pathway enrichment analysis showed specific enrichment in autophagy-apoptosis and mitochondrial pathways. These findings provide genetic evidence supporting a putative causal role of OSRGs on NDDs, offering mechanistic insights and potential therapeutic targets, and substantially advance the pathobiological understanding of NDDs.

Cuproptosis, a copper-dependent form of regulated cell death acting through lipoylated tricarboxylic acid (TCA) cycle proteins, has been proposed as a molecular link between type 2 diabetes and Alzheimer’s disease. We asked whether cuproptosis effector genes are dysregulated in a cell-type-specific manner in the human Alzheimer’s disease cortex, and whether any such signal survives controls for neuronal composition and disease specificity. Single-nucleus data from 21 prefrontal cortex donors were aggregated to donor-level pseudobulk within each cell type. Four independent bulk cohorts, each contributing one observation per donor, entered a random-effects meta-analysis. Adjustment for estimated neuronal content, competitive and expression-matched null gene-set testing, and comparison against Huntington’s disease and vascular dementia were applied as controls. The donor was the unit of replication throughout. No gene–cell-type pair survived correction across the 75 prespecified tests; PDHA1 in inhibitory neurons showed the largest nominal reduction (− 0.418, q = 0.829). In donor-level meta-analysis PDHA1 was lower in Alzheimer’s disease in all four cohorts (− 0.457, 95% CI − 0.712 to − 0.201, I²= 0%) but did not survive correction (q = 0.086). A post hoc lipoylation/pyruvate dehydrogenase/TCA module did reach the adjusted threshold (− 0.245, 95% CI − 0.363 to − 0.127, q = 0.035), whereas the copper modules pooled to zero and moved in opposite directions across cohorts. Comparable reductions occurred in Huntington’s disease and vascular dementia, and the disease-control contrasts were not significant. These transcriptional associations do not demonstrate cuproptosis, are not specific to Alzheimer’s disease, and are hypothesis-generating only.

Mitochondrial dysfunction is linked to sleep disorders in previous report, but the potential roles of specific genes remain unclear. This study aimed to dissect different subtype-specific genetic associations and their underlying mechanisms. A multi-omics Summary-data-based Mendelian Randomization (SMR) approach was performed to identify potential causal links between mitochondrial function-related genes and sleep disorders. We integrated GWAS data from FinnGen database (the discovery set), independent GWAS datasets (covering different sleep-disorder subtypes and used for validation), and cis-QTLs (including mQTLs, eQTLs, and pQTLs) to perform systematic exploration. Specially, we performed targeted validation of tissue-specific effects, leveraging gene expression data from disease-relevant brain regions within the GTEx database. Our SMR analysis identified mitochondrial function-related genes potentially modulating sleep disorders across biological layers, initially identifying 102 genes at the methylation level, 48 at the gene expression level, and 6 at the protein abundance level. Integrative analysis subsequently prioritized DCXR and ACADVL and revealed their distinct, subtype-specific associations. DCXR exhibited a protective role in sleep apnea while ACADVL showed a paradoxical risk conferring role in daytime sleepiness. In addition, the analysis identified an epigenetic regulatory mechanism for DCXR in which its expression and protein levels are modulated by DNA methylation. Finally, validation in brain-hypothalamus tissue confirmed DCXR as a significant potential protective factor (OR = 0.929, 95% CI: 0.887–0.973, P_HEIDI = 0.999, FDR = 0.2449). Our findings implicate key mitochondrial genes, particularly DCXR and ACADVL, in the pathophysiology of specific sleep disorder subtypes, highlighting potential avenues for precision medicine. Clinical trial number: Not applicable.

Platelet-derived growth factor subunit B (PDGFB) is a key regulator of vascular remodeling, angiogenesis, and blood–brain barrier integrity. Although elevated PDGFB levels have been reported after ischemic injury, whether stroke liability itself causally influences circulating PDGFB levels remains unclear. We performed a two-sample Mendelian randomization (MR) analysis to assess the causal effects of genetically predicted all stroke, ischemic stroke, and cardioembolic stroke on plasma PDGFB concentrations. Genetic instruments were obtained from large-scale GIGASTROKE genome-wide association studies, and outcome data were derived from a proteomics GWAS. Instruments were then filtered by removing variants associated with established cardiovascular risk factors in a phenome-wide screen and outliers identified by RadialMR. The inverse variance–weighted (IVW) method was used as the primary analysis, complemented by weighted median, weighted mode, and MR-Egger approaches. Sensitivity analyses included Cochran's Q statistics, MR-Egger intercept tests, single-SNP analyses, leave-one-out analyses, and MR-PRESSO. IVW analysis demonstrated a significant positive causal association between genetic liability to all stroke and plasma PDGFB levels (β = 0.209, SE = 0.062, 95% CI 0.088 to 0.331, p = 7.3 × 10⁻⁴). A similar association was observed for ischemic stroke (β = 0.155, SE = 0.059, 95% CI 0.039 to 0.270, p = 0.009), with directionally consistent results across sensitivity analyses. MR-Egger regression for ischemic stroke initially suggested pleiotropy.After removal of a radial-MR outlier (rs2289252), the intercept was attenuated and no longer statistically significant (− 0.0190, p = 0.282). In contrast, no evidence of a causal association was found between cardioembolic stroke liability and plasma PDGFB levels across all MR methods (β = − 0.078, SE = 0.087, 95% CI − 0.248 to 0.092, p = 0.368). These findings provide genetic evidence that liability to stroke, particularly ischemic stroke, is causally associated with increased circulating PDGFB levels, whereas cardioembolic stroke does not show such an effect. This suggests that elevated PDGFB reflects vascular responses specific to ischemic stroke rather than a general consequence of all stroke subtypes.

Mental and behavioural disorders substantially impair everyday functioning, yet the biological mechanisms through which the gut microbiome may contribute to psychiatric vulnerability remain insufficiently characterized. We jointly analysed genome-wide association study data for 473 gut microbial taxa, approximately 1,400 circulating metabolites, and seven mental and behavioural disorders, including schizophrenia, obsessive-compulsive disorder, post-traumatic stress disorder, attention-deficit/hyperactivity disorder, chronic depression, bulimia nervosa, and hypersomnia. Mendelian randomization was used to estimate genetically proxied associations among these traits, and two-step MR was used to evaluate candidate statistical mediation by circulating metabolites. We identified FDR-supported associations for eight microbial taxa across four disorders: UBA8904, Dorea, and Ruminococcus A sp000432335 with ADHD; Pseudomonas aeruginosa, Bifidobacterium kashiwanohense, and CAG-273 sp003534295 with chronic depression; Syntrophorhabdia with bulimia nervosa; and Aneurinibacillales with hypersomnia. Twelve circulating metabolites were statistically consistent with partial mediation of candidate microbiota-disorder associations. Glycocholate glucuronide (1) accounted for an estimated 5.95% of the Syntrophorhabdia-bulimia nervosa association, whereas 5-dodecenoate (12:1n7) was consistent with mediation of 8.28% of the inverse association between CAG-273 sp003534295 and chronic depression. Target enrichment prioritized lipid metabolism and neuroactive ligand-receptor interaction pathways for further study. The inverse association between genetically predicted 5-dodecenoate and depression was reproduced in an independent depression GWAS. These findings nominate candidate microbiota-metabolite pathways for mechanistic investigation; however, residual horizontal pleiotropy and linkage-disequilibrium-related confounding cannot be excluded, and the results should not be interpreted as definitive causal evidence.

Traumatic brain injury (TBI) is associated with complex transcriptional disturbances involving cortical suppression, neuroimmune responses, and altered neuroactive signaling. Although repetitive transcranial magnetic stimulation (rTMS) and acupuncture-related stimulation have been investigated as neuromodulatory strategies after brain injury, the transcriptomic features associated with combined rTMS and press-tack needle (PTN) stimulation remain incompletely understood. In this study, RNA sequencing was performed on prefrontal cortex tissue from Sham rats, TBI rats, and TBI rats treated with combined rTMS + PTN. Differentially expressed genes (DEGs), functional enrichment, pathway-gene interaction networks, protein-protein interaction networks, and gene set enrichment analysis (GSEA) were used to explore transcriptional alterations associated with TBI and combined intervention. TBI induced marked transcriptional changes in the prefrontal cortex, including genes enriched in neuroactive ligand-receptor interaction, calcium signaling, and injury-related pathways. Combined rTMS + PTN stimulation was associated with additional transcriptional remodeling, particularly involving immune-inflammatory pathways such as NF-κB signaling, IL-17 signaling, cytokine-cytokine receptor interaction, and Toll-like receptor signaling. Intersection analysis identified 55 shared TBI-associated and intervention-responsive genes as a candidate signature. Further PPI and GSEA analyses suggested that Nts/Ntsr1, Egr1, Drd1, and related neuroactive signaling molecules may participate in the transcriptional response to combined stimulation after TBI. These findings provide an exploratory RNA-seq-based framework for understanding NTSR1-associated neuroimmune and neuroactive molecular signatures after TBI. Targeted qRT-PCR assessment of selected neuroactive candidate genes, including Ntsrl, Egrl, and Drd1, provided complementary evidence of group-dependent expression differences in an independent animal cohort. Further protein-level and functional validation will be required to determine the causal relationships among these candidate molecules.

Postoperative delirium (POD) and Alzheimer’s disease (AD) are increasingly recognized as related neurocognitive conditions, but the aging-associated cell states that may connect them remain poorly defined. Here, we integrated two brain transcriptomic discovery datasets analyzed at single-cell/single-nucleus resolution, including a POD-related cohort (GSE291019) and an AD cohort (GSE129308), together with two independent peripheral-blood bulk transcriptomic datasets (GSE163943 and GSE63060), to identify aging-associated cellular programs and prioritize convergent molecular candidates. Across 184,168 high-quality cells, inhibitory neurons showed the most consistent aging-associated perturbation across the POD- and AD-related datasets. Re-clustering further identified three inhibitory-neuron subtypes, Inh_Neurons2, Inh_Neurons3, and Inh_Neurons5, with relatively high aging-related gene activity and preferential localization to later pseudotime states. Cross-platform integration of aging-associated inhibitory-neuron genes with a shared bulk DEG set identified four convergent candidates: RGL2, AKT1, SYK, and TNFSF13B. Among them, RGL2 emerged as the leading candidate, with the strongest downstream support concentrated in AD-related analyses. In two-sample Mendelian randomization, genetically predicted higher RGL2 expression was associated with increased AD risk, whereas the estimate for the delirium genome-wide association study proxy used for POD-related analyses was not significant. Pathway analyses further linked higher RGL2 expression to complement/coagulation and innate immune-inflammatory programs in AD-related analyses. These findings suggest a model in which POD and AD may partially intersect through aging-vulnerable inhibitory-neuron states and identify RGL2 as a prioritized candidate for downstream mechanistic investigation.

Parkinson’s disease (PD) is a progressive neurodegenerative disorder that affects over 12 million people worldwide. A central pathological feature is the accumulation of aggregated alpha-synuclein (αS) in Lewy bodies and Lewy neurites. Engineered αS variants such as 3K (E35K+E46K+E61K) and KLK (KTKEGV→KLKEGV in 6 repeats) have been shown to enhance membrane binding and aggregation propensity, contributing to cellular toxicity. To further investigate the impact of 3K and KLK on αS biology, we developed a sensitive assay in a human neuroblastoma model to assess expression levels and cytotoxicity. Relative to wild-type αS, the 3K mutant exhibited reduced steady-state expression and increased toxicity, consistent with prior reports. In contrast, the KLK mutant showed no marked change in protein expression but induced significantly higher toxicity, more than the 3K variant. Furthermore, stearoyl-CoA desaturase (SCD) inhibition partially rescued the toxicity of 3K and KLK αS, with 3K showing greater restoration of cell growth than KLK, validating the sensitivity of our live-cell assay to detect pharmacological responses. These findings underscore the utility of our assay in dissecting disease-relevant mechanisms and highlight the potential of engineered αS variants to model pathogenic features of PD. This platform offers a versatile tool for evaluating therapeutic strategies targeting αS aggregation and toxicity in PD and related synucleinopathies.

Obsessive-compulsive disorder (OCD) is linked to cortico-striato-thalamo-cortical circuit dysfunction, but molecular programs within striatal circuit nodes remain incompletely characterized. We tested whether translation, mitochondrial bioenergetics, and proteostasis show a coordinated transcriptomic signature in the OCD caudate. We reanalyzed postmortem caudate RNA-sequencing data from GSE262138 after retaining OCD cases and unaffected controls (OCD n = 27; control n = 85). Gene-level models adjusted for RNA integrity number and sex. Ranked gene statistics were used for pathway enrichment, module testing, expression-matched random-gene comparisons, sensitivity analyses, marker-score adjustment, and comparison with published OCD striatal literature. The caudate gene-level landscape showed a broad ranked-expression pattern. Pathway analysis identified recurrent lower expression of translation/ribosome, mitochondrial oxidative phosphorylation, electron-transport, and proteostasis-related terms across annotation systems. Translation/ribosome, mitochondrial/OXPHOS, and proteostasis modules showed lower average shifts relative to expression-matched random gene sets, and the direction remained consistent across sensitivity analyses. OCD caudate transcriptomic variation shows a pathway-level signature centered on translational, bioenergetic, and proteostatic programs. The results connect public postmortem caudate expression data with CSTC circuit biology and provide a focused molecular view of OCD-associated caudate dysfunction.