Neural Disorders Research Articles

Pathogenic mechanism and therapeutic intervention of impaired N7-methylguanosine (m7G) tRNA modification

Mutations modification enzymes including the tRNA N7-methylguanosine (m7G) methyltransferase complex component WDR4 were frequently found in patients with neural disorders, while the pathogenic mechanism and therapeutic intervention strategies are poorly explored. In this study, we revealed that patient-derived WDR4 mutation leads to temporal and cell-type-specific neural degeneration, and directly causes neural developmental disorders in mice. Mechanistically, WDR4 point mutation disrupts the interaction between WDR4 and METTL1 and accelerates METTL1 protein degradation. We further uncovered that impaired tRNA m7G modification caused by Wdr4 mutation decreases the mRNA translation of genes involved in mTOR pathway, leading to elevated endoplasmic reticulum stress markers, and increases neural cell apoptosis. Importantly, treatment with stress-attenuating drug Tauroursodeoxycholate (TUDCA) significantly decreases neural cell death and improves neural functions of the Wdr4 mutated mice. Moreover, adeno-associated virus mediated transduction of wild-type WDR4 restores METTL1 protein level and tRNA m7G modification in the mouse brain, and achieves long-lasting therapeutic effect in Wdr4 mutated mice. Most importantly, we further demonstrated that both TUDCA treatment and WDR4 restoration significantly improve the survival and functions of human iPSCs-derived neuron stem cells that harbor the patient's WDR4 mutation. Overall, our study uncovers molecular insights underlying WDR4 mutation in the pathogenesis of neural diseases and develops two promising therapeutic strategies for treatment of neural diseases caused by impaired tRNA modifications.

A Wireless Bi-Directional Brain–Computer Interface Supporting Both Bluetooth and Wi-Fi Transmission

Wireless neural signal transmission is essential for both neuroscience research and neural disorder therapies. However, conventional wireless systems are often constrained by low sampling rates, limited channel counts, and their support of only a single transmission mode. Here, we developed a wireless bi-directional brain–computer interface system featuring dual transmission modes. This system supports both low-power Bluetooth transmission and high-sampling-rate Wi-Fi transmission, providing flexibility for various application scenarios. The Bluetooth mode, with a maximum sampling rate of 14.4 kS/s, is well suited for detecting low-frequency signals, as demonstrated by both in vitro recordings of signals from 10 to 50 Hz and in vivo recordings of 16-channel local field potentials in mice. More importantly, the Wi-Fi mode, offering a maximum sampling rate of 56.8 kS/s, is optimized for recording high-frequency signals. This capability was validated through in vitro recordings of signals from 500 to 2000 Hz and in vivo recordings of single-neuron spike firings with amplitudes reaching hundreds of microvolts and high signal-to-noise ratios. Additionally, the system incorporates a wireless stimulation function capable of delivering current pulses up to 2.55 mA, with adjustable pulse width and polarity. Overall, this dual-mode system provides an efficient and flexible solution for both neural recording and stimulation applications.

Gold Nanorod-Embedded PDMS Micro-Pillar Array for Localized Photothermal Stimulation.

Gold nanorods (GNRs) are one of the most promising biomaterial choices for the photothermal activation of neurons due to their relative biocompatibility, unique photothermal properties, and broad optical tunability through their synthetic shape control. While photothermal stimulation using randomly accumulated GNRs successfully demonstrates the potential treatment of functional neural disorders by modulating the neuronal activities using localized heating, there are limited demonstrations to translate this new concept into large-arrayed neural stimulations. In this paper, we report an arrayed PDMS micropillar platform in which GNRs are embedded as pixel-like, arrayed photothermal stimulators at the tips of the pillars. The proposed platform will be able to localize GNRs at predetermined pillar positions and create thermal stimulations using near-infrared (NIR) light. This will address the limitations of randomly distributed GNR-based approaches. Furthermore, a flexible PDMS pillar structure will create intimate interfaces on target cells. By characterizing the spatiotemporal temperature change in the platform with rhodamine B dye, we have shown that the localized temperature can be optically modulated within 4°C, which is in the range of temperature variation required for neuromodulation using NIR light. We envision that our proposed platform has the potential to be applied as a photothermal, neuronal stimulation interface with high spatiotemporal resolution.

Structural and functional brain alterations in laryngeal dystonia: A coordinate-based activation likelihood estimation meta-analysis.

Laryngeal dystonia (LD) is an isolated, task-specific, focal dystonia characterized by intermittent spasms of laryngeal muscles impairing speech production. Although recent studies have demonstrated neural alterations in LD, the consistency of findings across studies is not well-established, limiting their translational applicability. We conducted a systematic literature search to identify studies reporting stereotactic coordinates of peak structural and functional abnormalities in LD patients compared to healthy controls, followed by a coordinate-based activation likelihood estimation meta-analysis. A total of 21 functional and structural neuroimaging studies, including 31 experiments in 521 LD patients and 448 healthy controls, met the study inclusion criteria. The multimodal meta-analysis of these studies identified abnormalities in the bilateral primary motor cortices, the left inferior parietal lobule and striatum, the right insula, and the supplementary motor area in LD patients compared to healthy controls. The meta-analytical findings reinforce the current view of dystonia as a neural network disorder and consolidate evidence for future investigations probing these targets with new therapies.

MAOA uVNTR Polymorphism in a Sample of Patients Diagnosed with Papillary Thyroid Cancer

Thyroid gland carcinoma (TGC), though only 1% of all carcinomas, is the most common endocrine neoplasm with an increasing incidence since the 1990s. Of the TGC types, papillary thyroid carcinoma (PTC) is the most common and has the best overall prognosis. Although primarily studied in various neural spectrum disorders, monoamine oxidase A (MAOA) may also contribute to cancer occurrence. This case control study assessed the prevalence of MAOA uVNTR polymorphism in PTC patients, compared its frequency with a healthy control, and assessed the variant’s impact on clinical features. The research participants consisted of 30 PTC patients (20 female, 10 male) over 18 years old who underwent thyroidectomy and radioiodine therapy at a Federal District private clinic and 30 paired and unrelated healthy volunteers (18 female, 12 male). The most frequent MAOA uVNTR alleles were 3R and 4R. Although no significant difference was detected in the genotypic distribution nor the PTC patients’ thyroglobulin, thyroid-stimulating hormone, and antithyroglobulin levels; body mass indexes; administered radiopharmaceutical (131I) doses; or biological sex, the presence of at least one 3R allele was associated with a larger tumor size (T3 + T4 staging). Thus, the 3R allele seems to be associated with PTC pathogenesis severity.

Cognitive Dysfunction in the Addictions (CDiA): A Neuron to Neighbourhood Collaborative Research Program on Executive Dysfunction and Functional Outcomes in Outpatients Seeking Treatment for Addiction.

Substance use disorders (SUDs) are pressing global public health problems. Executive functions (EFs) are prominently featured in mechanistic models of addiction. However, there remain significant gaps in our understanding of EFs in SUDs, including the dimensional relationships of EFs to underlying neural circuits, molecular biomarkers, disorder heterogeneity, and functional ability. To improve health outcomes for people with SUDs, interdisciplinary clinical, preclinical and health services research is needed to inform policies and interventions aligned with biopsychosocial models of addiction. Here, we introduce Cognitive Dysfunction in the Addictions (CDiA), an integrative team-science and translational research program, which aims to fill these knowledge gaps and facilitate research discoveries to enhance treatments for people living with SUDs. The CDiA Program comprises seven complementary interdisciplinary projects that aim to progress understanding of EF in SUDs and investigate new biological treatment approaches. The projects draw on a diverse sample of adults aged 18-60 (target N=400) seeking treatment for addiction, who are followed prospectively over one year to identify EF domains crucial to recovery. Projects 1-3 investigate SUD symptoms, brain circuits, and blood biomarkers and their associations with both EF domains (inhibition, working memory, and set-shifting) and functional outcomes (disability, quality of life). Projects 4 and 5 evaluate interventions for addiction and their impacts on EF: a clinical trial of repetitive transcranial magnetic stimulation and a preclinical study of potential new pharmacological treatments in rodents. Project 6 links EF to healthcare utilization and is supplemented with a qualitative investigation of EF-related barriers to treatment engagement for those with substance use concerns. Project 7 uses innovative whole-person modeling to integrate the multi-modal data generated across projects, applying clustering and deep learning methods to identify patient subtypes and drive future cross-disciplinary initiatives. The CDiA program has promise to bring scientific domains together to uncover the diverse ways in which EFs are linked to SUD severity and functional recovery. These findings, supported by emerging clinical, preclinical, health service, and whole-person modeling investigations, will facilitate future discoveries about cognitive dysfunction in addiction and could enhance the future clinical care of individuals seeking treatment for SUDs.

Genetic and Environmental Factors Co-Contributing to Behavioral Abnormalities in adnp/adnp2 Mutant Zebrafish.

Human mutations of ADNP and ADNP2 are known to be associated with neural developmental disorders (NDDs), including autism spectrum disorders (ASDs) and schizophrenia (SZ). However, the underlying mechanisms remain elusive. In this study, using CRISPR/Cas9 gene editing technology, we generated adnp and adnp2 mutant zebrafish models, which exhibited developmental delays, brain deficits, and core behavioral features of NDDs. RNA sequencing analysis of adnpa-/-; adnpb-/- and adnp2a-/-; adnp2b-/- larval brains revealed altered gene expression profiles affecting synaptic transmission, autophagy, apoptosis, microtubule dynamics, hormone signaling, and circadian rhythm regulation. Validation using whole-mount in situ hybridization (WISH) and real-time quantitative PCR (qRT-PCR) corroborated these findings, supporting the RNA-seq results. Additionally, loss of adnp and adnp2 resulted in significant downregulation of pan-neuronal HuC and neuronal fiber network α-Tubulin signals. Importantly, prolonged low-dose exposure to environmental endocrine disruptors (EEDs) aggravated behavioral abnormalities in adnp and adnp2 mutants. This comprehensive approach enhances our understanding of the complex interplay between genetic mutations and environmental factors in NDDs. Our findings provide novel insights and experimental foundations into the roles of adnp and adnp2 in neurodevelopment and behavioral regulation, offering a framework for future preclinical drug screening aimed at elucidating the pathogenesis of NDDs and related conditions.

A turn-on anthraquinone-derived colorimetric and fluorometric dual-mode probe for highly selective Hg2+ determination and bioimaging in living organisms

Mercury ion (Hg2+) is considered a harmful neurotoxin, and real-time monitoring of Hg2+ concentrations in environmental and biological samples is critical. Fluorescent probes are a rapidly emerging visualization tool owing to their simple design and good selectivity. Herein, a novel fluorescence (FL) probe 2-(4-((6-((quinolin-8-yloxy)methyl)pyridin-2-yl)methyl)piperazin-1-yl)anthracene-9,10-dione (QPPA) is designed using piperazine as a linker between the anthraquinone group, which serves as a fluorophore, and N4O as the Hg2+ ligand. The probe exhibits FL “turn-on” sensing of Hg2+ because the complex inhibits the photo-induced electron transfer (PET) process. Moreover, QPPA can overcome the invasion by other possible cations, resulting in a clear color change from orange to colorless with the addition Hg2+. The chelation of QPPA with Hg2+ in a 1:1 ratio. Subsequently, the theoretically determined binding sites of the ligand to Hg2+ are validated through 1H NMR titration. The in situQPPA–Hg2+ complex can be subjected to Hg2+ extraction following the introduction of S2− owing to its robust binding capacity. The exceptional limit of detection values for Hg2+ and S2− are obtained as 63.0 and 79.1 nM (S/N = 3), respectively. Moreover, QPPA can display bright red FL in the presence of Hg2+ in different biological specimens such as HeLa cells, zebrafish, onion root tip tissues, and water flea Daphnia carinata, further providing an effective strategy for environmental monitoring and bioimaging of Hg2+ in living organisms.

Neural Development and Repair Induced by Femtosecond Laser Stimulation.

Dendritic spines function as postsynaptic sites, receiving excitatory signals from presynaptic axons. The synaptic plasticity of spines underlies the refinement of neuronal circuits. Neural cognitive disorders are commonly associated with the impairment and elimination of dendritic spines. In this study, we report an all-optical method to activate dendritic spine growth and regeneration by a single short flash of femtosecond laser stimulation. The inhibited development and loss of spines can be rescued by a transient illumination of the laser inside a micrometer region of the soma by activating the extracellular signal-regulated kinase (ERK) signaling pathway. The rescued neurons exhibit function. Hence we provide a potential noninvasive method for the regeneration of dendritic spines.

Implant Design and Cervical Spinal Biomechanics and Neurorehabilitation: A Finite Element Investigation.

The cervical spine, pivotal for mobility and overall body function, can be affected by cervical spondylosis, a major contributor to neural disorders. Prevalent in both general and military populations, especially among pilots, cervical spondylosis induces pain and limits spinal capabilities. Anterior Cervical Discectomy and Fusion (ACDF) surgery, proposed by Cloward in the 1950s, is a promising solution for restoring natural cervical curvature. The study objective was to investigate the impacts of ACDF implant design on postsurgical cervical biomechanics and neurorehabilitation outcomes by utilizing a biofield head-neck finite element (FE) platform that can facilitate scenario-specific perturbations of neck muscle activations. This study addresses the critical need to enhance computational models, specifically FE modeling, for ACDF implant design. We utilized a validated head-neck FE model to investigate spine-implant biomechanical interactions. An S-shaped dynamic cage incorporating titanium (Ti) and polyetheretherketone (PEEK) materials was modeled at the C4/C5 level. The loading conditions were carefully designed to mimic helmet-to-helmet impact in American football, providing a realistic and challenging scenario. The analysis included intervertebral joint motion, disk pressure, and implant von Mises stress. The PEEK implant demonstrated an increased motion in flexion and lateral bending at the contiguous spinal (C4/C5) level. In flexion, the Ti implant showed a modest 5% difference under 0% activation conditions, while PEEK exhibited a more substantial 14% difference. In bending, PEEK showed a 24% difference under 0% activation conditions, contrasting with Ti's 17%. The inclusion of the head resulted in an average increase of 18% in neck angle and 14% in C4/C5 angle. Disk pressure was influenced by implant material, muscle activation level, and the presence of the head. Polyetheretherketone exhibited lower stress values at all intervertebral disc levels, with a significant effect at the C6/C7 levels. Muscle activation level significantly influenced disk stress at all levels, with higher activation yielding higher stress. Titanium implant consistently showed higher disk stress values than PEEK, with an orders-of-magnitude difference in von Mises stress. Excluding the head significantly affected disk and implant stress, emphasizing its importance in accurate implant performance simulation. This study emphasized the use of a biofidelic head-neck model to assess ACDF implant designs. Our results indicated that including neck muscles and head structures improves biomechanical outcome measures. Furthermore, unlike Ti implants, our findings showed that PEEK implants maintain neck motion at the affected level and reduce disk stresses. Practitioners can use this information to enhance postsurgery outcomes and reduce the likelihood of secondary surgeries. Therefore, this study makes an important contribution to computational biomechanics and implant design domains by advancing computational modeling and theoretical knowledge on ACDF-spine interaction dynamics.

Hypoxic Signal Transduction and Compensatory Mechanisms in the Neurovascular Unit.

Hypoxic hypoxia arises from an inadequate oxygen supply to the blood, resulting in reduced arterial oxygen partial pressure and a consequent decline in oxygen diffusion into tissue cells for utilization. This condition is characterized by diminished oxygen content in the blood, while the supply of other nutrients within the blood remains normal. The brain is particularly sensitive to oxygen deficiency, with varying degrees of hypoxic hypoxia resulting in different levels of neural functional disorder. Since the brain has a specific threshold range for the perception of hypoxic hypoxia, mild hypoxic hypoxia can trigger compensatory protective responses in the brain without affecting neural function. These hypoxic compensatory responses enable the maintenance of an adequate oxygen supply and energy substrates for neurons, thereby ensuring normal physiological functions. To further understand the hypoxic compensatory mechanisms of the central nervous system (CNS), this article explores the structural features of the brain's neurovascular unit model, hypoxic signal transduction, and compensatory mechanisms.

Aggregated Pattern Classification Method for improving neural disorder stage detection.

Neurological disorders pose a significant health challenge, and their early detection is critical for effective treatment planning and prognosis. Traditional classification of neural disorders based on causes, symptoms, developmental stage, severity, and nervous system effects has limitations. Leveraging artificial intelligence (AI) and machine learning (ML) for pattern recognition provides a potent solution to address these challenges. Therefore, this study focuses on proposing an innovative approach-the Aggregated Pattern Classification Method (APCM)-for precise identification of neural disorder stages. The APCM was introduced to address prevalent issues in neural disorder detection, such as overfitting, robustness, and interoperability. This method utilizes aggregative patterns and classification learning functions to mitigate these challenges and enhance overall recognition accuracy, even in imbalanced data. The analysis involves neural images using observations from healthy individuals as a reference. Action response patterns from diverse inputs are mapped to identify similar features, establishing the disorder ratio. The stages are correlated based on available responses and associated neural data, with a preference for classification learning. This classification necessitates image and labeled data to prevent additional flaws in pattern recognition. Recognition and classification occur through multiple iterations, incorporating similar and diverse neural features. The learning process is finely tuned for minute classifications using labeled and unlabeled input data. The proposed APCM demonstrates notable achievements, with high pattern recognition (15.03%) and controlled classification errors (CEs) (10.61% less). The method effectively addresses overfitting, robustness, and interoperability issues, showcasing its potential as a powerful tool for detecting neural disorders at different stages. The ability to handle imbalanced data contributes to the overall success of the algorithm. The APCM emerges as a promising and effective approach for identifying precise neural disorder stages. By leveraging AI and ML, the method successfully resolves key challenges in pattern recognition. The high pattern recognition and reduced CEs underscore the method's potential for clinical applications. However, it is essential to acknowledge the reliance on high-quality neural image data, which may limit the generalizability of the approach. The proposed method allows future research to refine further and enhance its interpretability, providing valuable insights into neural disorder progression and underlying biological mechanisms.

Coexistence of neural tube defects and spinal arteriovenous shunts: a case series and review of literature.

Spinal arteriovenous shunts and spinal dysraphism both have a different underlying cause, disease spectrum and developmental process; hence, these entities rarely coexist in a patient. Here, we reported four cases of coexistence of adult-onset spinal arteriovenous shunt and spinal dysraphism in the same patient along with their therapeutic embolisation. Additionally, we conducted an extensive literature review to explore the potential theories and explanations for this coexistence. We retrospectively searched our imaging database from January 2015 to December 2023 to identify instances of spinal arteriovenous shunts occurring in patients with spinal dysraphism or neural tube defect disorders. MRI and angiographic imaging, clinical presentation, treatment and follow-up were analysed. Four patients with arteriovenous fistula/shunt and spinal dysraphism were included in the study. The mean age of presentation was 35.5years. The most common symptoms were sensory disturbance and motor weakness. Arteriovenous fistula or shunt was located at the lumber region in one patient and at the sacral region in three cases. Two patients have a prior history of surgery in first decade. Two patients were treated with glue embolisation. The internal iliac artery was a common feeder in all cases. The rare coexistence of neural tube defects with spinal vascular abnormalities should be considered when assessing a middle-aged patient with neural tube defect and myelopathy. Correct diagnosis can help in treatment planning and thereby improve prognosis.

The crosstalk between oxidative stress and DNA damage induces neural stem cell senescence by HO-1/PARP1 non-canonical pathway

Neural stem cells play a crucial role in maintaining brain homeostasis. Neural stem cells senescence can lead to the decline of nerve repair and regeneration, causing brain aging and neurodegenerative diseases. However, the mechanism underlying neural stem cells senescence remains poorly understood. In this study, we report a novel HO-1/PARP1 non-canonical pathway highlighting how oxidative stress triggers the DNA damage response, ultimately leading to premature cellular senescence in neural stem cells. HO-1 acts as a sensor for oxidative stress, while PARP1 functions as a sensor for DNA damage. The simultaneous expression and molecular interaction of these two sensors can initiate a crosstalk of oxidative stress and DNA damage response processes, leading to the vicious cycle. The persistent activation of this pathway contributes to the senescence of neural stem cells, which in turn plays a crucial role in the progression of neurodegenerative diseases. Consequently, targeting this novel signaling pathway holds promise for the development of innovative therapeutic strategies and targets aimed at mitigating neural stem cells senescence-related disorders.

Synthesis of Lipidated Ligands and Formulation of Glia-Specific LNPs for RNAi-Mediated BBB Protection.

Pro-inflammatory polarization of microglia and astrocytes results in neuroinflammation and blood-brain barrier (BBB) disruption after a primary traumatic brain injury (TBI). Herein, we demonstrate that the dual-ligand functionalized lipid nanoparticles (AM31 LNPs) were actively and specifically internalized by microglia and astrocytes via mannose receptor (MR)- and adenosine receptor (AR)-mediated endocytosis, respectively, in a mouse model of TBI. Systemic administration of AM31 LNPs carrying siRNA against p65 resulted in internalization by the glial cells in the peri-infarct region and a robust knockdown of p65 at both mRNA and protein levels in these cells, leading to significant down-regulation of key pro-inflammatory cytokines and up-regulation of key anti-inflammatory cytokines. AM31 LNP-mediated silencing of p65 ameliorated TBI-induced BBB disruption. Our data proved that AM 31 LNP is a promising vehicle for RNA therapeutics for targeting microglia and astrocytes in neural disorder.

Acupuncture Therapy Modulating "Du" Channel Attenuates Ischemic Stroke-induced Disorders by Modulating REST-mediated miR-21/PDCD4 Signaling Transduction.

Acupuncture is a traditional Chinese therapy with treating potential against cognitive dysfunction. MicroRNA-21-3p (miR-21-3p) is well characterized for its benefits on neural tissues. The current study hypothesizes that the acupuncture aiming "Du" channel could attenuate IS-induced neural disorders by modulating the function of REST/miR-21-3p axis. Complications associated with IS are induced by a middle cerebral artery occlusion (MCAO) model in vivo. The disorders are then handled with the acupuncture with nimodipine as the positive control. It is found that the acupuncture improved cognitive function, reduced brain apoptosis, and increased the viable neuron number of model rats. Additionally, the production of cytokines is also suppressed by the acupuncture. At the molecular level, the level of miR-21-3p was up-regulated, while the level of REST was down-regulated by the acupuncture. The changes in miR-REST/21-3p contributed to the inhibition of PDCD4. Collectively, the findings in the current study highlight that miR-21-3p is associated with the anti-IS function of the acupuncture, which is mediated by the inhibition of REST.

Human cytomegalovirus infection impairs neural differentiation via repressing sterol regulatory element binding protein 2-mediated cholesterol biosynthesis

Congenital human cytomegalovirus (HCMV) infection is a major cause of abnormalities and disorders in the central nervous system (CNS) and/or the peripheral nervous system (PNS). However, the complete pathogenesis of neural differentiation disorders caused by HCMV infection remains to be fully elucidated. Stem cells from human exfoliated deciduous teeth (SHEDs) are mesenchymal stem cells (MSCs) with a high proliferation and neurogenic differentiation capacity. Since SHEDs originate from the neural crest of the early embryonic ectoderm, SHEDs were hypothesized to serve as a promising cell line for investigating the pathogenesis of neural differentiation disorders in the PNS caused by congenital HCMV infection. In this work, SHEDs were demonstrated to be fully permissive to HCMV infection and the virus was able to complete its life cycle in SHEDs. Under neurogenic inductive conditions, HCMV infection of SHEDs caused an abnormal neural morphology. The expression of stem/neural cell markers was also disturbed by HCMV infection. The impairment of neural differentiation was mainly due to a reduction of intracellular cholesterol levels caused by HCMV infection. Sterol regulatory element binding protein-2 (SREBP2) is a critical transcription regulator that guides cholesterol synthesis. HCMV infection was shown to hinder the migration of SREBP2 into nucleus and resulted in perinuclear aggregations of SREBP2 during neural differentiation. Our findings provide new insights into the prevention and treatment of nervous system diseases caused by congenital HCMV infection.

A neurotherapeutic approach with Lacticaseibacillus rhamnosus E9 on gut microbiota and intestinal barrier in MPTP-induced mouse model of Parkinson’s disease

The gut microbiota plays a crucial role in neural development and progression of neural disorders like Parkinson’s disease (PD). Probiotics have been suggested to impact neurodegenerative diseases via gut-brain axis. This study aims to investigate the therapeutic potential of Lacticaseibacillus rhamnosus E9, a high exopolysaccharide producer, on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)-induced mouse model of PD. C57BL/6 mice subjected to MPTP were fed L. rhamnosus E9 for fifteen days and sacrificed after the last administration. Motor functions were determined by open-field, catalepsy, and wire-hanging tests. The ileum and the brain tissues were collected for ELISA, qPCR, and immunohistochemistry analyses. The cecum content was obtained for microbiota analysis. E9 supplementation alleviated MPTP-induced motor dysfunctions accompanied by decreased levels of striatal TH and dopamine. E9 also reduced the level of ROS in the striatum and decreased the DAT expression while increasing the DR1. Furthermore, E9 improved intestinal integrity by enhancing ZO-1 and Occludin levels and reversed the dysbiosis of the gut microbiota induced by MPTP. In conclusion, E9 supplementation improved the MPTP-induced motor deficits and neural damage as well as intestinal barrier by modulating the gut microbiota in PD mice. These findings suggest that E9 supplementation holds therapeutic potential in managing PD through the gut-brain axis.

Reduction of Glyoxalase 1 Expression Links Fetal Methylmercury Exposure to Autism Spectrum Disorder Pathogenesis.

Glyoxalase 1 (Glo1) is an essential enzyme to detoxify methylglyoxal (MGO), a cytotoxic byproduct of glycolysis. Accumulating studies have shown an important role of Glo1 in regulating cortical development and neurogenesis, potentially contributing to the pathogenesis of autism spectrum disorder (ASD) when impaired. We have previously shown that prenatal exposure to non-apoptotic low-dose methylmercury (MeHg), an environmental pollutant, induces premature cortical neurogenesis and ASD-like behaviors in a rodent model. In this study, we aimed to determine the underlying molecular mechanisms that mediate prenatal MeHg-induced premature neuronal differentiation and abnormal neurodevelopment. Using single-cell RNA sequencing (scRNA-seq) and real-time quantitative PCR (RT-qPCR), we found that prenatal MeHg exposure at a non-apoptotic dose significantly reduced Glo1 gene expression in embryonic cultured radial glia precursors (RGPs). In cultured RGPs, the knockdown of Glo1 expression increased neuronal production at the expense of the cultured RGPs population, while overexpression of Glo1 restored MeHg-induced neuronal differentiation back to normal levels. Furthermore, we found that co-treatment with both MeHg and multiple MGO scavengers or a CREB inhibitor (iCREB) mitigated MeHg-induced premature neuronal differentiation, reinforcing the role of Glo1 and CREB in mediating MeHg-induced neuronal differentiation. Our findings demonstrate a direct link between MeHg exposure and expression of an ASD risk gene Glo1 in cortical development, supporting the important role of gene-environment interaction in contributing to the etiology of neural developmental disorders, such as ASD.

Neural crest development and disorders: from patient to model system and back again - the NEUcrest conference.

The neural crest (NC) is an embryonic multipotent and transitory population of cells that appears during late gastrulation/early neurulation in the developing embryos of vertebrate organisms. Often called "the fourth germ layer", the NC is characterised by incredible mobility, which allows the NC cells to migrate throughout the whole embryo, giving rise to an astonishing number of different derivatives in the adult organism, such as craniofacial skeleton, adrenal gland, enteric nervous system and melanocytes. Because of these properties, neurocristopathies (NCPs), which is the term used to classify genetic diseases associated with NC developmental defects, are often syndromic and, taken all together, are the most common type of genetic disease. The NEUcrest consortium is an EU funded innovative training network (ITN) that aims to study the NC and NCPs. In March 2024, the early stage researchers (ESRs) in the NEUcrest consortium organised an in-person conference for well-established and early career researchers to discuss new advances in the NC and NCPs field, starting from the induction of the NC, and then moving on to migration and differentiation processes they undergo. The conference focused heavily on NCPs associated with each of these steps. The conference also included events, such as a round table to discuss the future of the NC research, plus a talk by a person living with an NCP. This 3-day conference aimed to bring together the past, present and future of this field to try and unravel the mysteries of this unique cell population.