Journal of Molecular Neuroscience最新文献

As nociceptors, C-fibers play a critical role in maintaining host homeostasis under both physiological and pathological conditions. We previously demonstrated that C-fiber degeneration confers protection against respiratory syncytial virus (RSV) infection. However, a comprehensive investigation of the effects of C-fiber degeneration on the physiological state of the host remains unexplored. To address this gap, we established a C-fiber-degenerated (KCF) BALB/c mouse model and validated it by immunofluorescence staining of multiple organs. We monitored the body weight of KCF mice and performed 16S rRNA sequencing of their feces. And their brains, lungs, intestines, and spleen were subjected to section staining and RNA sequencing. Although no significant changes in body weight or tissue pathology were observed, KCF mice showed significant transcriptional alterations in the four examined organs. The lungs and intestines exhibited diminished proportions of resting mast cells, while the spleens displayed reduced proportions of monocytes. Functional enrichment analysis revealed the involvement of C-fibers in the production of immunoglobulin and changes in intestinal microbiota. Subsequent experiments confirmed a trend towards reduced globulin levels in the peripheral blood and marked alterations in the diversity and composition of intestinal microbiota. Integrated analysis of differentially expressed genes shared by all four organs identified the nucleotide-binding and oligomerization domain (NOD)-like receptor signaling pathway as a pivotal route by which C-fibers may influence these organs. In summary, this study elucidates the diverse effects of C-fibers on the host, extending our understanding in a multi-organ context. 

Alzheimer’s disease (AD), a progressive neurodegenerative disorder, is marked by memory loss, cognitive decline, and characteristic pathological features including β-amyloid (Aβ) plaques, tau tangles, and neuroinflammation. Despite extensive research, effective therapies remain elusive. Exosome/EVs-based therapeutics have emerged as a promising avenue for AD treatment. Neuron-derived exosomes/extracellular vesicles (EVs) (NDEs) and stem cell-derived exosomes/EVs exhibit neuroprotective effects by promoting Aβ degradation, modulating tau pathology, and reducing inflammation. Notably, NDEs carry insulin-degrading enzyme (IDE) and cellular prion proteins (PrPC), aiding Aβ clearance. However, exosomes also present challenges, such as the potential propagation of pathogenic tau and complement-mediated neurotoxicity. Neural and mesenchymal stem cell-derived exosomes further demonstrate therapeutic efficacy by altering amyloid precursor protein processing and activating PI3K/Akt/mTOR signaling to reduce AD pathology. Despite these advancements, clinical translation requires a deeper understanding of exosome/EVs biology, improved isolation techniques, and personalized strategies. Continued research may establish exosomes as a transformative approach in AD therapy.

De novo variants in the Activity-Dependent Neuroprotective Protein (ADNP) gene cause the autistic Helsmoortel-Van der Aa syndrome with patients showing mild to disastrous phenotypes impacting brain functioning, behavior, and organ functions. In this respect, two treatment strategies have been proposed to alleviate symptoms in patients with this syndrome: (1) the ADNP-derived octapeptide investigational drug NAP (davunetide), which enhances ADNP’s ability to target cytoskeletal deficits, and (2) subnarcotic levels of ketamine, which are suggested to increase endogenous ADNP mRNA levels. Here, we focus on the perspective of ketamine and investigated the transcriptomic response of low-dose and high-dose ketamine applications at different time points, experimentally controlled by the non-toxic drug NAP, in lymphoblastoid cell lines obtained from individuals with Helsmoortel-Van der Aa syndrome. Transcriptome profiling was performed at baseline conditions, followed by dose (low or high) and time (40 min or 4 h)-dependent ketamine application in patient and control lymphoblastoid cell lines. We showed that ketamine affected ADNP expression levels in a dose- and time-dependent manner with only toxic ketamine concentrations increasing ADNP protein levels. Ketamine application also triggered a transcriptomic response with profound gene expression alterations centered around processes such as immune response-regulating signaling pathways and cell fate commitment at low-dose ketamine, together with organelle assembly and cytoskeletal dysregulation at high doses. A parallel control experiment with NAP under the same experimental conditions did not induce detectable gene expression differences in patient-derived cell lines. The ketamine-induced cytoskeletal alterations were functionally studied using immunoblotting, showing a disturbed expression of α-tubulin, β-actin, and to a minor extent microtubule-associated protein EB3 in patient-derived lymphoblastoid cells. Ketamine upregulates wild-type ADNP transcript and protein levels in a dose- and time-dependent manner in patient-derived lymphoblastoid cell lines from individuals with Helsmoortel-Van der Aa syndrome, while inducing a transcriptomic response that affects key processes including immune system signaling and cytoskeletal organization.

Objectives: Many children with neurodevelopmental disorders (NDD) show complex, multidimensional impairments meeting criteria for multiple NDD, yet remain “diagnostically homeless” as DSM-5 lacks a Multidimensional Impairment (MDI) category. We investigated the prevalence of genetic abnormalities in such complex NDD cases. Methods:Between 2017 and 2019, we diagnosed MDI in 666 patients. Among them, 122 (18%) underwent genetic assessment (DNA microarrays, karyotype, gene panels, FISH, FMR1 testing, exome/genome sequencing). We used univariate analyses and clustering to explore associations between clinical dimensions and genetic findings. Results: Genetic abnormalities were identified in 78 patients. Of these:

1. (1)

   41 had known abnormalities usually linked to complex NDD (e.g., del22q11.2);

2. (2)

   16 had mutations associated with severe ASD/ID (e.g., GRIA3 on Xq25);

3. (3)

   11 showed novel abnormalities not previously linked to NDD (e.g., duplication Xq21.1 including POU3F4);

4. (4)

   10 had variants of uncertain significance.

Depending on classification, prevalence ranged from 47% (57/122, definite or predisposition) to 64% (78/122, including uncertain/possible pathogenic variants). Neither clinical dimensions nor severity clusters were associated with the presence of genetic abnormalities. Conclusion:Despite a referral bias toward severe cases, the high rate of genetic findings in this cohort underscores the need for more systematic genetic testing in complex NDD with multidimensional impairment.

This study investigated oxidative stress biomarkers in differentiating trichotillomania (TTM), obsessive–compulsive disorder (OCD), and healthy controls (HC), focusing on thiol-disulfide homeostasis, total oxidant status (TOS), total antioxidant status (TAS), and ischemia-modified albumin (IMA). A total of 68 adolescent females aged 10–18 were recruited and divided into three groups: TTM (n = 24), OCD (n = 21), and HC (n = 23). Oxidative stress biomarkers were assessed through blood analyses, including measurements of thiol-disulfide homeostasis, TOS, TAS, and IMA. Blood analyses revealed that TTM patients had significantly lower native and total thiol levels, a reduced native/total thiol ratio, and elevated disulfide levels compared to OCD and HC (p < 0.01). ROC analysis indicated that the native thiol/total thiol ratio effectively distinguished TTM from both HC and OCD with high accuracy. These findings reveal distinct oxidative stress patterns in TTM and OCD, with disrupted thiol-disulfide homeostasis in TTM and elevated oxidative burden in OCD. The discriminative power of the native thiol/total thiol ratio suggests molecular-level differences, which may inform the etiopathogenesis of TTM and support the development of targeted treatment strategies.

This study aims to develop and evaluate deep neural network (DNN) models for accurately predicting the recurrence risk of glioblastoma multiforme (GBM) to enhance individualized treatment strategies and improve patient outcomes. This study implemented DNN architectures optimized using a hybrid differential evolution neural network (HDE-NN) framework to forecast GBM recurrence risk, particularly in patients at advanced disease stages. The models were trained and validated on a multimodal dataset comprising genomic profiles, imaging-derived metrics, and longitudinal clinical records from 780 GBM patients. Data were sourced from The Cancer Genome Atlas (TCGA) and institutional repositories. Performance was benchmarked against conventional machine learning models, including support vector machines (SVM), random forests (RF), and standard DNNs. The models were implemented in Python. The proposed HDE-optimized DNN achieved an accuracy of 94%, precision of 92%, recall of 90%, F1 score of 91%, and an AUC-ROC of 0.96. These metrics significantly outperformed baseline models, with improvements of 6–12% across evaluation criteria. Confidence intervals (95%) were computed via tenfold cross-validation, confirming statistical robustness. This research introduces a high-performance and generalizable deep learning framework for GBM recurrence prediction. By incorporating multi-source clinical and genomic data, the model demonstrates superior predictive capacity over traditional methods. These findings support the integration of AI-driven tools into GBM care workflows to improve prognosis assessment and personalize therapeutic interventions.

Ataxin-1 (ATXN1) is a nuclear-cytoplasmic shuttling protein, which, when expanded in its polyglutamine coding stretch, causes the progressive neurodegenerative disease Spinocerebellar Ataxia Type 1 (SCA1). While the role of nuclear ATXN1 as a repressor of transcription and regulator of splicing is well studied, its potential cytoplasmic role is more ambiguous. We previously demonstrated mitochondrial dysfunction- including altered respiration and enhanced oxidative stress- is associated with early SCA1 pathogenesis in mice. Moreover, intervention with the electron transport chain substrate succinic acid ameliorated Purkinje cell atrophy and cerebellar behavioral deficits. We now hypothesize that mitochondrial dysfunction in SCA1 may be at least partially due to cytoplasmic interactions between ATXN1 and mitochondria, rather than a result of mutant ATXN1’s altered nuclear function. In order to characterize the extent of mitochondrial dysfunction due to mutant ATXN1, we turned to cerebellar-derived Daoy cells which endogenously express human wild type ATXN1. Our SCA1 Daoy model stably over-express phosphorylation-prone, nuclear-aggregating ATXN1[82]. Despite the short lifespan (~ 33 h), Daoy SCA1 cells reveal gross morphological, compositional, and physiological deficits. Conversely, expression in Daoy of a phosphorylation-resistant, cytoplasm-degradable, non-aggregating ATXN1 (ATXN1[82Q-A776]) selectively resulted in intermediate physiological phenotypes and altered mitochondrial protein composition. Finally, our meta-analysis of previously published data supports direct interactions between mutant polyglutamine-expanded ATXN1 and mitochondrial proteins involved in apoptosis, oxidative phosphorylation, composition, and transcription. Our data therefore suggest that irrespective of a disease context and ATXN1[82Q] nuclear aggregation, mitochondrial deficits occur. Overall, the results of this study show mutant ATXN1 can affect metabolic processes outside of its deleterious effect on transcription and splicing, and highlights its multifaceted and multicompartmental function.

This study aimed to elucidate the potential role of serine proteases and their associated regulatory molecules in the etiopathogenesis of autism spectrum disorder (ASD) and to assess their relationship with symptom severity and specific behavioral domains in children diagnosed with ASD. A cross-sectional design was employed, including 44 children aged 2 to 6 years with a confirmed diagnosis of ASD and 43 age- and sex-matched typically developing children as controls. Behavioral assessments were conducted using the Childhood Autism Rating Scale (CARS), the Autism Behavior Checklist (ABC), and the Repetitive Behavior Scale-Revised, Turkish Version (RBS-R-TV). Serum concentrations of motopsin, agrin, C-terminal agrin fragment (CAF), tissue plasminogen activator (tPA), neuroserpin, and plasminogen activator inhibitor-1 (PAI-1) were determined using enzyme-linked immunosorbent assay (ELISA). Serum levels of all analyzed molecules were significantly reduced in the ASD group compared to controls (p < 0.05 for all). Although no significant associations were observed between total ASD severity scores and biomarker concentrations, notable correlations emerged between specific behavioral subdomains and select biomarkers. Motopsin levels exhibited a moderate positive correlation with the “imitation” subdomain of CARS and the “sensory” subdomain of ABC. Conversely, agrin levels demonstrated moderate inverse correlations with “listening response,” “taste–smell-touch response and use,” and “activity level” subdomains of CARS. PAI-1 levels showed a significant negative correlation with the “self-injurious behavior” subdomain of RBS-R-TV. The findings suggest that serine proteases and their modulators implicated in synaptic remodeling and neuroplasticity may contribute to the underlying neurobiological mechanisms of ASD. The observed domain-specific associations support the hypothesis that ASD comprises heterogeneous neurodevelopmental trajectories, and that peripheral biochemical markers reflecting these pathways may aid in the identification of ASD subtypes and guide personalized therapeutic strategies.

Aspartate, a key excitatory neurotransmitter, has shown conflicting links to cognitive disorders like Alzheimer’s disease (AD) and mild cognitive impairment (MCI). Given its role in brain function, studying its relationship with amyloid-beta (Aβ) accumulation may provide important insights into these conditions. This study is the first to examine the link between serum aspartate levels, Aβ accumulation in key brain regions, and cognitive function (via ADAS-Cog) across cognitively normal (n = 113), MCI (n = 283), and AD (n = 24) participants. The results showed significant increases in Aβ accumulation across all brain regions from CN to MCI and AD groups (overall p < 0.001; pairwise p ≤ 0.001). In individuals with MCI, elevated aspartate levels were inversely associated with Aβ accumulation in the frontal (β = − 0.122, p = 0.041) and temporal regions (β = − 0.128, p = 0.032), but this relationship was lost after adjusting for age, gender, education, handedness, and ApoE ɛ4, ɛ3, and ɛ2 genotypes. Further analysis identified age and ApoE ɛ4, ɛ3 status as key modifiers of the aspartate–Aβ relationship in MCI. Mediation analysis revealed that higher serum aspartate levels were associated with better cognitive function, potentially mediated by reduced Aβ accumulation in the frontal (β = − 0.037) and temporal lobes (β = − 0.043) in MCI, but this effect disappeared after adjusting for demographic factors and ApoE genotypes. Overall, higher serum aspartate levels may be associated with reduced Aβ accumulation and improved cognitive outcomes in MCI, with age and ApoE genotypes acting as key confounders.

The adult cerebellum retains a small Sox2/prominin-1 NSC pool whose fate is shaped by developmental cues and the glutamatergic milieu. We argue that glutamate excitotoxicity is the dominant negative regulator of this niche and Purkinje cell survival because it forms self-reinforcing loops. Spillover activates extrasynaptic GluN2B/2D-NMDARs, silencing CREB/PI3K–Akt and driving sustained (Ca^{2+}) influx; mitochondria translate this load into mPTP opening and ROS bursts, creating a (Ca^{2+})–ROS feedback that accelerates death. Oxidative stress and energy failure also depress EAAT1/2 clearance, elevating glutamate and re-activating eNMDARs. Loss of Purkinje cells withdraws Sonic Hedgehog support, shrinking the proliferative granule-precursor pool—another vicious cycle. A countervailing axis (synaptic GluN2A/2C and BDNF/TrkB) is muted by extrasynaptic drive. Cerebellar neurospheres model these gradients and readouts. We outline a triple strategy to break the loops: selective eNMDAR blockade, EAAT enhancement, and Sonic Hedgehog restoration.