The cure rate for chronic neurodegenerative diseases remains low,creating an urgent need for improved intervention methods.Recent studies have shown that enhancing mitochondrial function can mitigate the effects of th...The cure rate for chronic neurodegenerative diseases remains low,creating an urgent need for improved intervention methods.Recent studies have shown that enhancing mitochondrial function can mitigate the effects of these diseases.This paper comprehensively reviews the relationship between mitochondrial dysfunction and chronic neurodegenerative diseases,aiming to uncover the potential use of targeted mitochondrial interventions as viable therapeutic options.We detail five targeted mitochondrial intervention strategies for chronic neurodegenerative diseases that act by promoting mitophagy,inhibiting mitochondrial fission,enhancing mitochondrial biogenesis,applying mitochondria-targeting antioxidants,and transplanting mitochondria.Each method has unique advantages and potential limitations,making them suitable for various therapeutic situations.Therapies that promote mitophagy or inhibit mitochondrial fission could be particularly effective in slowing disease progression,especially in the early stages.In contrast,those that enhance mitochondrial biogenesis and apply mitochondria-targeting antioxidants may offer great benefits during the middle stages of the disease by improving cellular antioxidant capacity and energy metabolism.Mitochondrial transplantation,while still experimental,holds great promise for restoring the function of damaged cells.Future research should focus on exploring the mechanisms and effects of these intervention strategies,particularly regarding their safety and efficacy in clinical settings.Additionally,the development of innovative mitochondria-targeting approaches,such as gene editing and nanotechnology,may provide new solutions for treating chronic neurodegenerative diseases.Implementing combined therapeutic strategies that integrate multiple intervention methods could also enhance treatment outcomes.展开更多
Amyotrophic lateral sclerosis(ALS)is a progressive neurodegenerative disease marked by motor neuron(MN)degeneration,neuromuscular junction disruption,and muscle atrophy,ultimately leading to paralysis and death.Despit...Amyotrophic lateral sclerosis(ALS)is a progressive neurodegenerative disease marked by motor neuron(MN)degeneration,neuromuscular junction disruption,and muscle atrophy,ultimately leading to paralysis and death.Despite extensive research,no effective treatment exists,highlighting the need to elucidate mechanisms driving ALS pathogenesis.About 90%of ALS cases are sporadic ALS and lack a clear genetic cause;the remaining 10%are familial ALS,associated with mutations in over 25 genes.The most common mutations are in superoxide dismutase 1(SOD1)and C9ORF72,with rarer variants in FUS,TARDBP,TBK1,and VCP.展开更多
Based on the split hopkinson pressure bar(SHPB)tests results,the cubic specimens have been numerically modeled in this paper to investigate the impact of key factors,such as the rise time,duration,and incident pulse s...Based on the split hopkinson pressure bar(SHPB)tests results,the cubic specimens have been numerically modeled in this paper to investigate the impact of key factors,such as the rise time,duration,and incident pulse shape,on achieving stress uniformity.After analysis,the paper provides actionable methods aimed at optimizing the conditions for stress uniformity within the cubic specimen.Finally,the lateral inertia effect of cubic specimen has been scrutinized to address the existing gap in this academic area.展开更多
Objective The associations of serum trace element levels with disease progression and survival duration were assessed in individuals diagnosed with sporadic amyotrophic lateral sclerosis(sALS)in China.Methods Clinical...Objective The associations of serum trace element levels with disease progression and survival duration were assessed in individuals diagnosed with sporadic amyotrophic lateral sclerosis(sALS)in China.Methods Clinical data,including diagnostic indicators,clinical characteristics,Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised(ALSFRS-R)scores,and serum concentrations of calcium(Ca),magnesium(Mg),iron(Fe),copper(Cu),and zinc(Zn),were collected for hospitalized patients with sALS between 2018 and 2021.Correlation analysis,random forest analysis,and the Gehan-Breslow-Wilcoxon test were used to evaluate the relations between serum trace element levels,disease progression,and survival duration.Results Lower serum Ca levels and higher Mg levels were observed in patients with ALSFRS-R scores<39.Serum Mg was significantly negatively correlated with ALSFRS-R,trunk,and respiratory scores.Serum Cu and Zn also showed significant negative correlations with the respiratory score,whereas Ca and Fe were not significantly correlated with the ALSFRS-R score.The serum levels of Ca,Mg,Cu,Zn,and Fe remained consistent regardless of the site of disease onset.ALSFRS-R analysis revealed that serum Ca and Mg had a substantial effect on the total ALSFRS-R score,with serum Mg significantly influencing the course of the disease.Notably,low serum Mg levels were associated with extended survival times in patients with sALS.Conclusion Serum levels of Ca and Mg play critical roles in the progression of sALS,and a reduced serum Mg level is related to an extended survival time.展开更多
Non-right-handedness(NRH),encompassing left-handedness and mixed-handedness,has been frequently reported at elevated rates in individuals with various psychiatric disorders.The consistency of this association across m...Non-right-handedness(NRH),encompassing left-handedness and mixed-handedness,has been frequently reported at elevated rates in individuals with various psychiatric disorders.The consistency of this association across multiple conditions and its underlying mechanisms is the subject of ongoing investigation.This review synthesized current evidence to explore the association between NRH and psychiatric disorders from epidemiological,genetic,and neurobiological perspectives.We systematically identified and appraised relevant literature investigating NRH prevalence in psychiatric populations and potential explanatory mechanisms.Epidemiological evidence indicates an elevated prevalence of NRH,particularly within neurodevelopmental disorders.Potential contributing mechanisms identified include early developmental disruptions,shared genetic predispositions,and atypical patterns of brain lateralization.While the association between NRH and psychiatric conditions,especially neurodevelopmental disorders,is evident,the causal pathways and relative contributions of identified mechanisms are complex and debated.This review highlighted key areas requiring further research to elucidate these relationships.展开更多
As a controllable power generation method requiring no energy storage,Ocean Thermal Energy Conversion(OTEC)technology demonstrates characteristics of abundant reserves,low pollution,and round-the-clock stable operatio...As a controllable power generation method requiring no energy storage,Ocean Thermal Energy Conversion(OTEC)technology demonstrates characteristics of abundant reserves,low pollution,and round-the-clock stable operation.The free-standing cold-water pipe(CWP)in the system withstands various complex loads during operation,posing potential failure risks.To reveal the deformation and stress mechanisms of OTEC CWPs,this study first analyzes wave particle velocity and acceleration to determine wave loads at different water depths.Based on the Euler-Bernoulli beam model,a quasi-static load calculation model for OTEC CWPs was established.The governing equations were discretized using the finite difference method,and matrix equations were solved to analyze bending deformation,bending moments,and surface stresses at discrete points along the pipe.Results indicate that water depths within 50 m represent a critical zone where wave particle velocity,acceleration,and wave loads exhibit significant variations in harmonic patterns,while beyond 50 m depth wave loads decrease linearly.Ocean currents and surface wind-driven currents substantially influence the CWP’s lateral displacement.Considering the effect of clump weights,the maximum lateral displacement occurs at 600–800 m below sea level.Utilizing large-wall-thickness high-strength pipes at the top section significantly enhances the structural safety of the CWP system.展开更多
The growing recognition of the role of genetics in the development of amyotrophic lateral sclerosis is evident.However,there has yet to be a comprehensive analysis of the clinical characteristics and genetics of famil...The growing recognition of the role of genetics in the development of amyotrophic lateral sclerosis is evident.However,there has yet to be a comprehensive analysis of the clinical characteristics and genetics of familial amyotrophic lateral sclerosis in an Asian population.This study aimed to provide an in-depth analysis of the clinical features and genetic spectrum of familial amyotrophic lateral sclerosis over 15 years in a clinic-based cohort of patients from the Chinese mainland.Enrollment of 302 amyotrophic lateral sclerosis families from 28 provinces was undertaken from January 2008 to September 2023.A group-based trajectory model for disease progression based on amyotrophic lateral sclerosis Functional Rating Scale-Revised(ALSFRS-R)scores was validated using bootstrap internal validation in patients with familial amyotrophic lateral sclerosis,as well as patients with sporadic amyotrophic lateral sclerosis(matched at a 1:4 ratio,with replacement).DNA samples from 244 index patients were screened for variants in the pathogenic genes SOD1,FUS,TDP43,and C9ORF72,of which 146 were also subjected to genome-wide next-generation sequencing.Gene-level burden analysis was used to evaluate the distribution of rare variants in the cohort.We found that rapid dynamic disease progression was associated with an older age at onset,shorter diagnostic delay,lower body mass index,bulbar onset,and≥1 affected first-degree relative.Certain attributes,such as age at onset and time from onset to diagnosis,had comparable impacts on the clinical progression trajectories of both familial amyotrophic lateral sclerosis and sporadic amyotrophic lateral sclerosis.Harboring pathogenic/likely pathogenic variants in amyotrophic lateral sclerosis-causative genes reduced the age of onset of familial amyotrophic lateral sclerosis.Among the patients with familial amyotrophic lateral sclerosis,17.8%possessed≥2 pathogenic/likely pathogenic variants.Sequencing kernel association test analysis showed that the SOD1 rare variant burden(P=1.3e-15)was associated with a significant risk of familial amyotrophic lateral sclerosis.Our findings conclusively confirmed the clinical features and genetic spectrum of familial amyotrophic lateral sclerosis over 15 years in a clinical cohort from China,contributing to a deeper understanding of genotype-phenotype relationships in familial amyotrophic lateral sclerosis.This comprehensive evaluation of specific clinical characteristics,clinical prognosis,and genetic variants of amyotrophic lateral sclerosis based on detailed clinical and genetic information may lead to the development of genotype-specific treatment approaches.展开更多
Detecting biomarkers in body fluids by optical lateral flow immune assay(LFIA) technology provides rapid access to disease information for early diagnosis.LFIA is based on an antigen-antibody reaction and is rapidly b...Detecting biomarkers in body fluids by optical lateral flow immune assay(LFIA) technology provides rapid access to disease information for early diagnosis.LFIA is based on an antigen-antibody reaction and is rapidly becoming the preferred choice of physicians and patients for point-of-care testing due to its simplicity,cost-effectiveness,and rapid detection.Observing the optical signal change from the colloidal gold of the traditional LFIA strip has been widely applied for various biomarkers detection in body fluids.Despite the significant progress,rapid real-time detection of color changes in the colloidal gold by the naked eye still faces many limitations,such as large errors and the inability to quantify and accurately detect.New optical LFIA strip technology has emerged in recent years to extend its application scenarios for achieving quantitative detection such as fluorescence,afterglow,and chemiluminescence.Herein,we summarized the development of optical LFIA technology from single to hyphenated optical signals for biomarkers detection in body fluids from invasive and non-invasive sources.Moreover,the challenge and outlook of optical LFIA strip technology are highlighted to inspire the designing of next-generation diagnostic platforms.展开更多
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the progressive degeneration of upper and lower motor neurons in the brainstem and spinal cord,leading to muscle weakness,para...Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the progressive degeneration of upper and lower motor neurons in the brainstem and spinal cord,leading to muscle weakness,paralysis,and respiratory failure (Morgan and Orrell,2016).展开更多
The presence or absence of adult neural stem cells in the mammalian forebrain ependyma has been debated for two decades.In this study,we performed single-cell RNA sequencing to investigate the cellular composition of ...The presence or absence of adult neural stem cells in the mammalian forebrain ependyma has been debated for two decades.In this study,we performed single-cell RNA sequencing to investigate the cellular composition of the ependymal surface of the adult mouse forebrain using whole mounts of lateral walls of lateral ventricles.We identified 12 different cell subtypes in the ependymal surface.Immunocytochemical analyses revealed that CD133^(+)multi-ciliated cells comprised 67.6%of ependymal cells,while the remaining 32.4%were CD133^(-).CD133^(+)ependymal cells can be further classified into FOXJ1^(+)/SOX2^(+)/ACTA2^(+)cells,FLT1^(+)/CD31^(+)/CLDN5^(+)endothelial-like cells,and PDGFRB^(+)/VTN^(+)/NG2^(+)pericyte-like cells,as well as endothelial-pericyte-like cells and Foxj1^(+)endothelial-like cells.CD133^(-)ependymal cells can be further divided into endothelial-like cells,Foxj1^(+)ependymal cells,Foxj1^(+)endothelial-like cells,pericyte-like cells,endothelial-pericyte-like cells,VIM^(+)cells,and cells negative for all of these markers.This comprehensive profiling confirms the heterogeneity of the ependymal surface in the adult mouse forebrain.Debate regarding whether adult ependymal cells contain neural stem cells has arisen because different researchers have examined different populations of ependymal cells.Our study provides a new perspective for investigation of clinical endogenous neural stem cells,ultimately paving the way for stem cell therapies in neurological diseases.展开更多
Motor neuron diseases are sporadic or inherited fatal neurodegenerative conditions.They selectively affect the upper and/or lower motor neurons in the brain and spinal cord and feature a slow onset and a subacute cour...Motor neuron diseases are sporadic or inherited fatal neurodegenerative conditions.They selectively affect the upper and/or lower motor neurons in the brain and spinal cord and feature a slow onset and a subacute course contingent upon the site of damage.The main types include amyotrophic lateral sclerosis,progressive muscular atrophy,primary lateral sclerosis,and progressive bulbar palsy,the pathological processes of which are largely identical,with the main disparity lying in the location of the lesions.Amyotrophic lateral sclerosis is the representative condition in this group of diseases,while other types are its variants.Hence,this article mainly focuses on the advancements and challenges in drug research for amyotrophic lateral sclerosis but also briefly addresses several other important degenerative motor neuron diseases.Although the precise pathogenesis remains elusive,recent advancements have shed light on various theories,including gene mutation,excitatory amino acid toxicity,autoimmunology,and neurotrophic factors.The US Food and Drug Administration has approved four drugs for use in delaying the progression of amyotrophic lateral sclerosis:riluzole,edaravone,AMX0035,and tofersen,with the latter being the most recent to receive approval.However,following several phaseⅢtrials that failed to yield favorable outcomes,AMX0035 has been voluntarily withdrawn from both the US and Canadian markets.This article presents a comprehensive summary of drug trials primarily completed between January 1,2023,and June 30,2024,based on data sourced from clinicaltrials.gov.Among these trials,five are currently in phaseⅠ,seventeen are in phaseⅡ,and eleven are undergoing phaseⅢevaluation.Notably,24 clinical trials are now investigating potential disease-modifying therapy drugs,accounting for the majority of the drugs included in this review.Some promising drugs being investigated in preclinical studies,such as ATH-1105,are included in our analysis,and another review in frontiers in gene therapy and immunotherapy has demonstrated their therapeutic potential for motor neuron diseases.This article was written to be an overview of research trends and treatment prospects related to motor neuron disease drugs,with the aim of highlighting the latest potentialities for clinical therapy.展开更多
Lateral movement represents the most covert and critical phase of Advanced Persistent Threats(APTs),and its detection still faces two primary challenges:sample scarcity and“cold start”of new entities.To address thes...Lateral movement represents the most covert and critical phase of Advanced Persistent Threats(APTs),and its detection still faces two primary challenges:sample scarcity and“cold start”of new entities.To address these challenges,we propose an Uncertainty-Driven Graph Embedding-Enhanced Lateral Movement Detection framework(UGEA-LMD).First,the framework employs event-level incremental encoding on a continuous-time graph to capture fine-grained behavioral evolution,enabling newly appearing nodes to retain temporal contextual awareness even in the absence of historical interactions and thereby fundamentally mitigating the cold-start problem.Second,in the embedding space,we model the dependency structure among feature dimensions using a Gaussian copula to quantify the uncertainty distribution,and generate augmented samples with consistent structural and semantic properties through adaptive sampling,thus expanding the representation space of sparse samples and enhancing the model’s generalization under sparse sample conditions.Unlike static graph methods that cannot model temporal dependencies or data augmentation techniques that depend on predefined structures,UGEA-LMD offers both superior temporaldynamic modeling and structural generalization.Experimental results on the large-scale LANL log dataset demonstrate that,under the transductive setting,UGEA-LMD achieves an AUC of 0.9254;even when 10%of nodes or edges are withheld during training,UGEA-LMD significantly outperforms baseline methods on metrics such as recall and AUC,confirming its robustness and generalization capability in sparse-sample and cold-start scenarios.展开更多
Superoxide dismutase 1(SOD1)is a thermodynamically stable,zinc and copper binding homodimeric enzyme responsible for breaking down superoxide radicals.More than 200,mostly missense,mutations spread throughout the SOD1...Superoxide dismutase 1(SOD1)is a thermodynamically stable,zinc and copper binding homodimeric enzyme responsible for breaking down superoxide radicals.More than 200,mostly missense,mutations spread throughout the SOD1 gene are associated with the fatal neurodegenerative disease,amyotrophic lateral sclerosis(ALS).A unifying feature of ALS-associated SOD1 mutations is the destabilization of the SOD1 protein structure,increasing the propensity for misfolding and subsequent pathological aggregation.Post-mortem analysis of SOD1-associated ALS tissue shows the accumulation of misfolded SOD1 protein and ubiquitinated SOD1 inclusions within motor neurons.Misfolded SOD1 accumulation and aggregates are implicated in cellular dysfunction via a number of disparate but critical processes,including endoplasmic reticulum stress,oxidative damage,proteasome dysfunction,axonal transport abnormalities and synaptic dysfunction;culminating in motor neuron degeneration associated with ALS.展开更多
Maintaining a stable body temperature is essential for survival.Multiple brain regions contribute to thermoregulation,but their specific characteristics and underlying neural mechanisms in the coordination of thermore...Maintaining a stable body temperature is essential for survival.Multiple brain regions contribute to thermoregulation,but their specific characteristics and underlying neural mechanisms in the coordination of thermoregulation are not fully clarified.Here,we reveal the distinct roles of two preoptic subregions in warm defense in mice:the anterior ventromedial preoptic area(VMPO)and the ventral part of the lateral preoptic nucleus(vLPO).VMPO vesicular glutamate transporter 2(Vglut2)neurons exhibited dramatic responses to rising temperatures,producing a marked decrease in core temperature by warm defense responses.In contrast,excitatory and inhibitory vLPO neurons responded gently to warm stimuli,exerting moderate effects on warm defense.Further postsynaptic tracing and caspase ablation identified distinct cell type-specific downstream targets in the dorsomedial hypothalamus(DMH)mediating these different warm defense responses.Taken together,our findings reveal distinct yet complementary pathways in the preoptic DMH network that enable both rapid and fine-tuned regulation of body temperature under elevated thermal conditions.展开更多
Ataxin-2 is a 140 kDa cytoplasmic multifunctional protein that plays fundamental roles in diverse cellular mechanisms(Costa et al.,2024).Although widely studied in the context of the neurodegenerative diseases spinoce...Ataxin-2 is a 140 kDa cytoplasmic multifunctional protein that plays fundamental roles in diverse cellular mechanisms(Costa et al.,2024).Although widely studied in the context of the neurodegenerative diseases spinocerebellar ataxia type 2(SCA2)and amyotrophic lateral sclerosis(ALS),ataxin-2 functions span far beyond its pathogenic properties in the disease context(Figure 1).In fact,it has a wide range of biological functions that include RNA metabolism,translation regulation,stress response,endocytosis,calcium signaling,and the control of circadian rhythm.In this perspective,we highlight the main roles of ataxin-2 protein,which are described in detail in Costa et al.(2024).展开更多
N umerous neurological disorders negatively impact the nervous system,either through loss of neurons or by disrupting the normal functioning of neural networks.These impairments manifest as cognitive defects,memory lo...N umerous neurological disorders negatively impact the nervous system,either through loss of neurons or by disrupting the normal functioning of neural networks.These impairments manifest as cognitive defects,memory loss,behavioral abnormalities,and motor dysfunctions.Decades of research have significantly advanced our understanding of the pathophysiology underlying neurodegene rative diseases,including Alzheimer's disease(AD),Parkinson's disease,amyotrophic lateral sclerosis,and others.展开更多
Neurodegenerative diseases(neurodegenerative disorders)are marked by the progressive degeneration of the structure and function of the central nervous system.They may res ult in the deterioration of cognitive,motor,an...Neurodegenerative diseases(neurodegenerative disorders)are marked by the progressive degeneration of the structure and function of the central nervous system.They may res ult in the deterioration of cognitive,motor,and functional abilities.Diseases such as Alzheimer s disease,Parkinson's disease,Huntington's disease,and amyotrophic lateral sclerosis represent some of the most prominent examples of neurodegenerative disorders.Des pite scientific advancement in understanding disease pathology and prognosis,the therapeutic strategies available for management remain limited.In recent years,microRNAs,small non-coding RNA molecules,have emerged as key players in the pathogenesis of neurodegenerative disorde rs.Therefo re,understanding how these microRNAs affect disease pathology and pathway signaling is essential,and may open microRNAs as new avenues for potential therapeutic intervention.This review explores the role of microRNAs in va rious neurodegenerative diseases,discuss how microRNAs affect signaling pathways,and examine the potential of microRNAs as therapeutic targets.展开更多
Amyotrophic lateral sclerosis is characterized by the progressive loss of motor neurons.Early-stage axonal dysfunction,rather than central nervous system injury,plays a key role in the disease process.However,the mole...Amyotrophic lateral sclerosis is characterized by the progressive loss of motor neurons.Early-stage axonal dysfunction,rather than central nervous system injury,plays a key role in the disease process.However,the molecular mechanisms underlying this dysfunction remain unclear.To investigate the relationship between peripheral immune dysregulation and axonal dysfunction in amyotrophic lateral sclerosis,we recruited 372 patients within the first 12 months of sporadic amyotrophic lateral sclerosis onset between January 2018 and May 2024.We collected peripheral immune markers at baseline,including total leukocytes,lymphocytes,monocytes,neutrophils,basophils,eosinophils,and platelets.We also calculated four derived ratios:neutrophil-to-lymphocyte ratio,platelet-to-lymphocyte ratio,lymphocyte-to-monocyte ratio,and systemic immune inflammation index.Multivariate analysis,adjusted for confounding factors,revealed that higher counts of total leukocytes and neutrophils,as well as higher neutrophil-related ratios,including the neutrophil to lymphocyte ratio and the systemic immune inflammation index,were significantly correlated with higher compound muscle action potential scores.Stratified analyses revealed that these associations varied by age and sex.Furthermore,mediation analysis demonstrated that axonal dysfunction plays a significant role in the relationship between immune markers and disease progression.These findings emphasize the critical role that peripheral immune dysregulation plays in amyotrophic lateral sclerosis progression by mediating peripheral nerve injury,particularly in the early stages of the disease.This study highlights the importance of the peripheral nervous system in the early stages of amyotrophic lateral sclerosis and provides new insights into disease mechanisms and potential therapeutic targets.展开更多
N^(6)-methyladenosine RNA methylation,an essential post-transcriptional modification,dynamically regulates RNA metabolism and plays a crucial role in neuronal function.Growing evidence suggests that dysregulated N^(6)...N^(6)-methyladenosine RNA methylation,an essential post-transcriptional modification,dynamically regulates RNA metabolism and plays a crucial role in neuronal function.Growing evidence suggests that dysregulated N^(6)-methyladenosine modification contributes to the pathogenesis of neurodegenerative diseases,including Alzheimer’s disease,Parkinson’s disease,multiple sclerosis,and amyotrophic lateral sclerosis.However,the precise mechanisms by which N^(6)-methyladenosine modification influences these conditions remain unclear.This review summarizes the role of m6A modification and its associated regulators in neurodegeneration,focusing on their involvement in key pathological processes.In Alzheimer’s disease,m6A modification contributes to synaptic dysfunction,mitochondrial damage,and neuronal apoptosis.Evidence from APP/PS1,5xFAD,tau transgenic,and Drosophila models demonstrates that regulators such as methyltransferase-like 3 and fat mass and obesity-associated protein influence Alzheimer’s disease progression through neuroinflammation,circular RNAs dysregulation,and autophagy-related mechanisms.In Parkinson’s disease,altered N^(6)-methyladenosine regulator expression affects dopaminergic neuron survival and stress responses by modulating mRNA stability and autophagy-related lncRNAs.In multiple sclerosis and amyotrophic lateral sclerosis,N^(6)-methyladenosine affects immune activation,myelin repair,and the regulation of disease-associated genes such as TDP-43.Beyond N^(6)-methyladenosine,other RNA methylation modifications-such as m1A,m5C,m7G,uracil,and pseudouridine-are implicated in neurodegenerative diseases through their regulation of mitochondrial function,RNA metabolism,and neuronal stress responses.Additionally,N^(6)-methyladenosine exhibits cell type-specific functions:in microglia,it regulates inflammatory activation and phagocytic function;in astrocytes,it modulates metabolic homeostasis and glutamate-associated neurotoxicity;in neurons,it affects synaptic function and neurodegeneration-related gene expression;and in adult neural stem cells,it controls differentiation,neurogenesis,and cognitive plasticity.Recently,several small-molecule inhibitors targeting methyltransferase-like 3 or fat mass and obesity-associated protein have been developed to modulate N^(6)-methyladenosine modification,providing new opportunities for disease intervention,with the targeting of N⁶-methyladenosine-related pathways emerging as a promising therapeutic strategy.However,challenges persist in optimizing the specificity and delivery of these therapeutic approaches.展开更多
基金partly supported by the Yan’an University Qin Chuanyuan“Scientist+Engineer”Team Special Fund,No.2023KXJ-012(to YL)Yan’an University Transformation of Scientific and Technological Achievements Fund,No.2023CGZH-001(to YL)+2 种基金College Students Innovation and Entrepreneurship Training Program,Nos.D2023158,202410719056(to XS,JM)Yan’an University Production and Cultivation Project,No.CXY202001(to YL)Kweichow Moutai Hospital Research and Talent Development Fund Project,No.MTyk2022-25(to XO)。
文摘The cure rate for chronic neurodegenerative diseases remains low,creating an urgent need for improved intervention methods.Recent studies have shown that enhancing mitochondrial function can mitigate the effects of these diseases.This paper comprehensively reviews the relationship between mitochondrial dysfunction and chronic neurodegenerative diseases,aiming to uncover the potential use of targeted mitochondrial interventions as viable therapeutic options.We detail five targeted mitochondrial intervention strategies for chronic neurodegenerative diseases that act by promoting mitophagy,inhibiting mitochondrial fission,enhancing mitochondrial biogenesis,applying mitochondria-targeting antioxidants,and transplanting mitochondria.Each method has unique advantages and potential limitations,making them suitable for various therapeutic situations.Therapies that promote mitophagy or inhibit mitochondrial fission could be particularly effective in slowing disease progression,especially in the early stages.In contrast,those that enhance mitochondrial biogenesis and apply mitochondria-targeting antioxidants may offer great benefits during the middle stages of the disease by improving cellular antioxidant capacity and energy metabolism.Mitochondrial transplantation,while still experimental,holds great promise for restoring the function of damaged cells.Future research should focus on exploring the mechanisms and effects of these intervention strategies,particularly regarding their safety and efficacy in clinical settings.Additionally,the development of innovative mitochondria-targeting approaches,such as gene editing and nanotechnology,may provide new solutions for treating chronic neurodegenerative diseases.Implementing combined therapeutic strategies that integrate multiple intervention methods could also enhance treatment outcomes.
文摘Amyotrophic lateral sclerosis(ALS)is a progressive neurodegenerative disease marked by motor neuron(MN)degeneration,neuromuscular junction disruption,and muscle atrophy,ultimately leading to paralysis and death.Despite extensive research,no effective treatment exists,highlighting the need to elucidate mechanisms driving ALS pathogenesis.About 90%of ALS cases are sporadic ALS and lack a clear genetic cause;the remaining 10%are familial ALS,associated with mutations in over 25 genes.The most common mutations are in superoxide dismutase 1(SOD1)and C9ORF72,with rarer variants in FUS,TARDBP,TBK1,and VCP.
基金Funded by the National Natural Science Foundation of China(Nos.52278518 and 51938011)the Natural Science Foundation of the Jiangsu Higher Education Institutions of China(No.24KJB560021)。
文摘Based on the split hopkinson pressure bar(SHPB)tests results,the cubic specimens have been numerically modeled in this paper to investigate the impact of key factors,such as the rise time,duration,and incident pulse shape,on achieving stress uniformity.After analysis,the paper provides actionable methods aimed at optimizing the conditions for stress uniformity within the cubic specimen.Finally,the lateral inertia effect of cubic specimen has been scrutinized to address the existing gap in this academic area.
文摘Objective The associations of serum trace element levels with disease progression and survival duration were assessed in individuals diagnosed with sporadic amyotrophic lateral sclerosis(sALS)in China.Methods Clinical data,including diagnostic indicators,clinical characteristics,Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised(ALSFRS-R)scores,and serum concentrations of calcium(Ca),magnesium(Mg),iron(Fe),copper(Cu),and zinc(Zn),were collected for hospitalized patients with sALS between 2018 and 2021.Correlation analysis,random forest analysis,and the Gehan-Breslow-Wilcoxon test were used to evaluate the relations between serum trace element levels,disease progression,and survival duration.Results Lower serum Ca levels and higher Mg levels were observed in patients with ALSFRS-R scores<39.Serum Mg was significantly negatively correlated with ALSFRS-R,trunk,and respiratory scores.Serum Cu and Zn also showed significant negative correlations with the respiratory score,whereas Ca and Fe were not significantly correlated with the ALSFRS-R score.The serum levels of Ca,Mg,Cu,Zn,and Fe remained consistent regardless of the site of disease onset.ALSFRS-R analysis revealed that serum Ca and Mg had a substantial effect on the total ALSFRS-R score,with serum Mg significantly influencing the course of the disease.Notably,low serum Mg levels were associated with extended survival times in patients with sALS.Conclusion Serum levels of Ca and Mg play critical roles in the progression of sALS,and a reduced serum Mg level is related to an extended survival time.
基金supported by a grant from NIH(R01AI132695)to RM。
文摘Chronic wasting disease—a prion disease affecting cervids:Many neurological conditions,including Alzheimer's and Parkinson's diseases,amyotrophic lateral sclerosis,frontotemporal dementias,among others,are caused by the accumulation of misfolded proteins in the brain.These diseases affect not only humans,but also animals.
文摘Non-right-handedness(NRH),encompassing left-handedness and mixed-handedness,has been frequently reported at elevated rates in individuals with various psychiatric disorders.The consistency of this association across multiple conditions and its underlying mechanisms is the subject of ongoing investigation.This review synthesized current evidence to explore the association between NRH and psychiatric disorders from epidemiological,genetic,and neurobiological perspectives.We systematically identified and appraised relevant literature investigating NRH prevalence in psychiatric populations and potential explanatory mechanisms.Epidemiological evidence indicates an elevated prevalence of NRH,particularly within neurodevelopmental disorders.Potential contributing mechanisms identified include early developmental disruptions,shared genetic predispositions,and atypical patterns of brain lateralization.While the association between NRH and psychiatric conditions,especially neurodevelopmental disorders,is evident,the causal pathways and relative contributions of identified mechanisms are complex and debated.This review highlighted key areas requiring further research to elucidate these relationships.
基金funded by Nansha District Science and Technology Project(Grant Number.2024ZD008)funded by China Geological Survey(Grant number:No.DD20230066,DD20242659).
文摘As a controllable power generation method requiring no energy storage,Ocean Thermal Energy Conversion(OTEC)technology demonstrates characteristics of abundant reserves,low pollution,and round-the-clock stable operation.The free-standing cold-water pipe(CWP)in the system withstands various complex loads during operation,posing potential failure risks.To reveal the deformation and stress mechanisms of OTEC CWPs,this study first analyzes wave particle velocity and acceleration to determine wave loads at different water depths.Based on the Euler-Bernoulli beam model,a quasi-static load calculation model for OTEC CWPs was established.The governing equations were discretized using the finite difference method,and matrix equations were solved to analyze bending deformation,bending moments,and surface stresses at discrete points along the pipe.Results indicate that water depths within 50 m represent a critical zone where wave particle velocity,acceleration,and wave loads exhibit significant variations in harmonic patterns,while beyond 50 m depth wave loads decrease linearly.Ocean currents and surface wind-driven currents substantially influence the CWP’s lateral displacement.Considering the effect of clump weights,the maximum lateral displacement occurs at 600–800 m below sea level.Utilizing large-wall-thickness high-strength pipes at the top section significantly enhances the structural safety of the CWP system.
基金supported by the Natural Science Foundation of Beijing,Nos.7244428(to WZ)and 7222215(to JH)the Peking University Medicine Sailing Program forYoung Scholars’Scientific and Technological Innovation,No.BMU2023YFJHPY034(to WZ)+4 种基金the National Natural Science Foundation of China,Nos.81873784,82071426(to DF),and81974197(to JH)the Clinical Cohort Construction Program of Peking University Third Hospital,No.BYSYDL2019002(to DF)Beijing Physician-Scientist TrainingProgram,No.BJPSTP-2024-03(to JH)the China Postdoctoral Science Foundation,Nos.2022TQ0014(to LX),2022M720284(to LX)the E-Town Cooperation&Development Foundation,No.YCXJ-JZ-2023-017(to LX).
文摘The growing recognition of the role of genetics in the development of amyotrophic lateral sclerosis is evident.However,there has yet to be a comprehensive analysis of the clinical characteristics and genetics of familial amyotrophic lateral sclerosis in an Asian population.This study aimed to provide an in-depth analysis of the clinical features and genetic spectrum of familial amyotrophic lateral sclerosis over 15 years in a clinic-based cohort of patients from the Chinese mainland.Enrollment of 302 amyotrophic lateral sclerosis families from 28 provinces was undertaken from January 2008 to September 2023.A group-based trajectory model for disease progression based on amyotrophic lateral sclerosis Functional Rating Scale-Revised(ALSFRS-R)scores was validated using bootstrap internal validation in patients with familial amyotrophic lateral sclerosis,as well as patients with sporadic amyotrophic lateral sclerosis(matched at a 1:4 ratio,with replacement).DNA samples from 244 index patients were screened for variants in the pathogenic genes SOD1,FUS,TDP43,and C9ORF72,of which 146 were also subjected to genome-wide next-generation sequencing.Gene-level burden analysis was used to evaluate the distribution of rare variants in the cohort.We found that rapid dynamic disease progression was associated with an older age at onset,shorter diagnostic delay,lower body mass index,bulbar onset,and≥1 affected first-degree relative.Certain attributes,such as age at onset and time from onset to diagnosis,had comparable impacts on the clinical progression trajectories of both familial amyotrophic lateral sclerosis and sporadic amyotrophic lateral sclerosis.Harboring pathogenic/likely pathogenic variants in amyotrophic lateral sclerosis-causative genes reduced the age of onset of familial amyotrophic lateral sclerosis.Among the patients with familial amyotrophic lateral sclerosis,17.8%possessed≥2 pathogenic/likely pathogenic variants.Sequencing kernel association test analysis showed that the SOD1 rare variant burden(P=1.3e-15)was associated with a significant risk of familial amyotrophic lateral sclerosis.Our findings conclusively confirmed the clinical features and genetic spectrum of familial amyotrophic lateral sclerosis over 15 years in a clinical cohort from China,contributing to a deeper understanding of genotype-phenotype relationships in familial amyotrophic lateral sclerosis.This comprehensive evaluation of specific clinical characteristics,clinical prognosis,and genetic variants of amyotrophic lateral sclerosis based on detailed clinical and genetic information may lead to the development of genotype-specific treatment approaches.
基金supported by the National Natural Science Foundation of China (Nos.22234005,22494632,22404081)the Natural Science Foundation of Jiangsu Province (Nos.BK20222015,BK20240534)。
文摘Detecting biomarkers in body fluids by optical lateral flow immune assay(LFIA) technology provides rapid access to disease information for early diagnosis.LFIA is based on an antigen-antibody reaction and is rapidly becoming the preferred choice of physicians and patients for point-of-care testing due to its simplicity,cost-effectiveness,and rapid detection.Observing the optical signal change from the colloidal gold of the traditional LFIA strip has been widely applied for various biomarkers detection in body fluids.Despite the significant progress,rapid real-time detection of color changes in the colloidal gold by the naked eye still faces many limitations,such as large errors and the inability to quantify and accurately detect.New optical LFIA strip technology has emerged in recent years to extend its application scenarios for achieving quantitative detection such as fluorescence,afterglow,and chemiluminescence.Herein,we summarized the development of optical LFIA technology from single to hyphenated optical signals for biomarkers detection in body fluids from invasive and non-invasive sources.Moreover,the challenge and outlook of optical LFIA strip technology are highlighted to inspire the designing of next-generation diagnostic platforms.
文摘Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the progressive degeneration of upper and lower motor neurons in the brainstem and spinal cord,leading to muscle weakness,paralysis,and respiratory failure (Morgan and Orrell,2016).
基金supported by the State Key Program of the National Natural Science Foundation of China,No.82030035(to YES)Peak Disciplines(Type IV)of Institutions of Higher Learning in Shanghai(to LZ).
文摘The presence or absence of adult neural stem cells in the mammalian forebrain ependyma has been debated for two decades.In this study,we performed single-cell RNA sequencing to investigate the cellular composition of the ependymal surface of the adult mouse forebrain using whole mounts of lateral walls of lateral ventricles.We identified 12 different cell subtypes in the ependymal surface.Immunocytochemical analyses revealed that CD133^(+)multi-ciliated cells comprised 67.6%of ependymal cells,while the remaining 32.4%were CD133^(-).CD133^(+)ependymal cells can be further classified into FOXJ1^(+)/SOX2^(+)/ACTA2^(+)cells,FLT1^(+)/CD31^(+)/CLDN5^(+)endothelial-like cells,and PDGFRB^(+)/VTN^(+)/NG2^(+)pericyte-like cells,as well as endothelial-pericyte-like cells and Foxj1^(+)endothelial-like cells.CD133^(-)ependymal cells can be further divided into endothelial-like cells,Foxj1^(+)ependymal cells,Foxj1^(+)endothelial-like cells,pericyte-like cells,endothelial-pericyte-like cells,VIM^(+)cells,and cells negative for all of these markers.This comprehensive profiling confirms the heterogeneity of the ependymal surface in the adult mouse forebrain.Debate regarding whether adult ependymal cells contain neural stem cells has arisen because different researchers have examined different populations of ependymal cells.Our study provides a new perspective for investigation of clinical endogenous neural stem cells,ultimately paving the way for stem cell therapies in neurological diseases.
基金supported by the National Key Research and Development Program of China,No.2022YFC2703101(to YC)the National Natural Science Fundation of China,No.82371422(to YC)+1 种基金the National Innovation and Entrepreneurship Training Program for College Students,No.202310611408(to XW)the 1·3·5 Project for Disciplines of Excellence Clinical Research Fund,West China Hospital,Sichuan University,No.2023HXFH032(to YC)。
文摘Motor neuron diseases are sporadic or inherited fatal neurodegenerative conditions.They selectively affect the upper and/or lower motor neurons in the brain and spinal cord and feature a slow onset and a subacute course contingent upon the site of damage.The main types include amyotrophic lateral sclerosis,progressive muscular atrophy,primary lateral sclerosis,and progressive bulbar palsy,the pathological processes of which are largely identical,with the main disparity lying in the location of the lesions.Amyotrophic lateral sclerosis is the representative condition in this group of diseases,while other types are its variants.Hence,this article mainly focuses on the advancements and challenges in drug research for amyotrophic lateral sclerosis but also briefly addresses several other important degenerative motor neuron diseases.Although the precise pathogenesis remains elusive,recent advancements have shed light on various theories,including gene mutation,excitatory amino acid toxicity,autoimmunology,and neurotrophic factors.The US Food and Drug Administration has approved four drugs for use in delaying the progression of amyotrophic lateral sclerosis:riluzole,edaravone,AMX0035,and tofersen,with the latter being the most recent to receive approval.However,following several phaseⅢtrials that failed to yield favorable outcomes,AMX0035 has been voluntarily withdrawn from both the US and Canadian markets.This article presents a comprehensive summary of drug trials primarily completed between January 1,2023,and June 30,2024,based on data sourced from clinicaltrials.gov.Among these trials,five are currently in phaseⅠ,seventeen are in phaseⅡ,and eleven are undergoing phaseⅢevaluation.Notably,24 clinical trials are now investigating potential disease-modifying therapy drugs,accounting for the majority of the drugs included in this review.Some promising drugs being investigated in preclinical studies,such as ATH-1105,are included in our analysis,and another review in frontiers in gene therapy and immunotherapy has demonstrated their therapeutic potential for motor neuron diseases.This article was written to be an overview of research trends and treatment prospects related to motor neuron disease drugs,with the aim of highlighting the latest potentialities for clinical therapy.
基金supported by the Zhongyuan University of Technology Discipline Backbone Teacher Support Program Project(No.GG202417)the Key Research and Development Program of Henan under Grant 251111212000.
文摘Lateral movement represents the most covert and critical phase of Advanced Persistent Threats(APTs),and its detection still faces two primary challenges:sample scarcity and“cold start”of new entities.To address these challenges,we propose an Uncertainty-Driven Graph Embedding-Enhanced Lateral Movement Detection framework(UGEA-LMD).First,the framework employs event-level incremental encoding on a continuous-time graph to capture fine-grained behavioral evolution,enabling newly appearing nodes to retain temporal contextual awareness even in the absence of historical interactions and thereby fundamentally mitigating the cold-start problem.Second,in the embedding space,we model the dependency structure among feature dimensions using a Gaussian copula to quantify the uncertainty distribution,and generate augmented samples with consistent structural and semantic properties through adaptive sampling,thus expanding the representation space of sparse samples and enhancing the model’s generalization under sparse sample conditions.Unlike static graph methods that cannot model temporal dependencies or data augmentation techniques that depend on predefined structures,UGEA-LMD offers both superior temporaldynamic modeling and structural generalization.Experimental results on the large-scale LANL log dataset demonstrate that,under the transductive setting,UGEA-LMD achieves an AUC of 0.9254;even when 10%of nodes or edges are withheld during training,UGEA-LMD significantly outperforms baseline methods on metrics such as recall and AUC,confirming its robustness and generalization capability in sparse-sample and cold-start scenarios.
基金Motor Neuron Disease Research Australia in the form of a Bill Gole Postdoctoral Fellowship(PDF2307)FightMND in the form of Drug Development Grants(DDG-159 and DDG137 to JSL)。
文摘Superoxide dismutase 1(SOD1)is a thermodynamically stable,zinc and copper binding homodimeric enzyme responsible for breaking down superoxide radicals.More than 200,mostly missense,mutations spread throughout the SOD1 gene are associated with the fatal neurodegenerative disease,amyotrophic lateral sclerosis(ALS).A unifying feature of ALS-associated SOD1 mutations is the destabilization of the SOD1 protein structure,increasing the propensity for misfolding and subsequent pathological aggregation.Post-mortem analysis of SOD1-associated ALS tissue shows the accumulation of misfolded SOD1 protein and ubiquitinated SOD1 inclusions within motor neurons.Misfolded SOD1 accumulation and aggregates are implicated in cellular dysfunction via a number of disparate but critical processes,including endoplasmic reticulum stress,oxidative damage,proteasome dysfunction,axonal transport abnormalities and synaptic dysfunction;culminating in motor neuron degeneration associated with ALS.
基金supported by the National Natural Science Foundation of China(32171001,32371050,and 82371554).
文摘Maintaining a stable body temperature is essential for survival.Multiple brain regions contribute to thermoregulation,but their specific characteristics and underlying neural mechanisms in the coordination of thermoregulation are not fully clarified.Here,we reveal the distinct roles of two preoptic subregions in warm defense in mice:the anterior ventromedial preoptic area(VMPO)and the ventral part of the lateral preoptic nucleus(vLPO).VMPO vesicular glutamate transporter 2(Vglut2)neurons exhibited dramatic responses to rising temperatures,producing a marked decrease in core temperature by warm defense responses.In contrast,excitatory and inhibitory vLPO neurons responded gently to warm stimuli,exerting moderate effects on warm defense.Further postsynaptic tracing and caspase ablation identified distinct cell type-specific downstream targets in the dorsomedial hypothalamus(DMH)mediating these different warm defense responses.Taken together,our findings reveal distinct yet complementary pathways in the preoptic DMH network that enable both rapid and fine-tuned regulation of body temperature under elevated thermal conditions.
基金Cure CSB ProjectViljem Julijan Association for Children with Rare Diseases(Slovenia)+1 种基金Algarve Biomedical Center Research Institute(ABC-Ri)AC received a PhD fellowship from the Portuguese Science and Technology Foundation(FCT)#2020.07892.BD.
文摘Ataxin-2 is a 140 kDa cytoplasmic multifunctional protein that plays fundamental roles in diverse cellular mechanisms(Costa et al.,2024).Although widely studied in the context of the neurodegenerative diseases spinocerebellar ataxia type 2(SCA2)and amyotrophic lateral sclerosis(ALS),ataxin-2 functions span far beyond its pathogenic properties in the disease context(Figure 1).In fact,it has a wide range of biological functions that include RNA metabolism,translation regulation,stress response,endocytosis,calcium signaling,and the control of circadian rhythm.In this perspective,we highlight the main roles of ataxin-2 protein,which are described in detail in Costa et al.(2024).
基金supported by the National Institute on Aging(Nos.AG000723 and AG000578)(to VAB)the Fondation Sante(No.19656),Greece 2.0+1 种基金the National Recovery and Resilience Plan’s flagship program TAEDR-0535850the European Research Council(No.101077374-Synapto Mitophagy)(to KP)。
文摘N umerous neurological disorders negatively impact the nervous system,either through loss of neurons or by disrupting the normal functioning of neural networks.These impairments manifest as cognitive defects,memory loss,behavioral abnormalities,and motor dysfunctions.Decades of research have significantly advanced our understanding of the pathophysiology underlying neurodegene rative diseases,including Alzheimer's disease(AD),Parkinson's disease,amyotrophic lateral sclerosis,and others.
基金1RO1EY032959-01 from NIH,Leonard A Mann Chair Endowment Fund,from the University of Dayton(to AS)Knights Templar Eye Foundation grant(to MS)。
文摘Neurodegenerative diseases(neurodegenerative disorders)are marked by the progressive degeneration of the structure and function of the central nervous system.They may res ult in the deterioration of cognitive,motor,and functional abilities.Diseases such as Alzheimer s disease,Parkinson's disease,Huntington's disease,and amyotrophic lateral sclerosis represent some of the most prominent examples of neurodegenerative disorders.Des pite scientific advancement in understanding disease pathology and prognosis,the therapeutic strategies available for management remain limited.In recent years,microRNAs,small non-coding RNA molecules,have emerged as key players in the pathogenesis of neurodegenerative disorde rs.Therefo re,understanding how these microRNAs affect disease pathology and pathway signaling is essential,and may open microRNAs as new avenues for potential therapeutic intervention.This review explores the role of microRNAs in va rious neurodegenerative diseases,discuss how microRNAs affect signaling pathways,and examine the potential of microRNAs as therapeutic targets.
基金Natural Science Foundation of Beijing,No.7244428(to WZ)Peking University Medicine Sailing Program for Young Scholars’Scientific and Technological Innovation,No.BMU2023YFJHPY034(to WZ)+1 种基金the National Natural Science Foundation of China,Nos.81873784(to DF),82071426(to DF)Clinical Cohort Construction Program of Peking University Third Hospital,Nos.BYSYDL2019002(to DF)and BYSYZD2021004(to DF).
文摘Amyotrophic lateral sclerosis is characterized by the progressive loss of motor neurons.Early-stage axonal dysfunction,rather than central nervous system injury,plays a key role in the disease process.However,the molecular mechanisms underlying this dysfunction remain unclear.To investigate the relationship between peripheral immune dysregulation and axonal dysfunction in amyotrophic lateral sclerosis,we recruited 372 patients within the first 12 months of sporadic amyotrophic lateral sclerosis onset between January 2018 and May 2024.We collected peripheral immune markers at baseline,including total leukocytes,lymphocytes,monocytes,neutrophils,basophils,eosinophils,and platelets.We also calculated four derived ratios:neutrophil-to-lymphocyte ratio,platelet-to-lymphocyte ratio,lymphocyte-to-monocyte ratio,and systemic immune inflammation index.Multivariate analysis,adjusted for confounding factors,revealed that higher counts of total leukocytes and neutrophils,as well as higher neutrophil-related ratios,including the neutrophil to lymphocyte ratio and the systemic immune inflammation index,were significantly correlated with higher compound muscle action potential scores.Stratified analyses revealed that these associations varied by age and sex.Furthermore,mediation analysis demonstrated that axonal dysfunction plays a significant role in the relationship between immune markers and disease progression.These findings emphasize the critical role that peripheral immune dysregulation plays in amyotrophic lateral sclerosis progression by mediating peripheral nerve injury,particularly in the early stages of the disease.This study highlights the importance of the peripheral nervous system in the early stages of amyotrophic lateral sclerosis and provides new insights into disease mechanisms and potential therapeutic targets.
基金supported by the National Nature Science Foundation of China(General Program),Nos.82271237,82071218(both to JC),and 82230042(to ZY)the Foundation of Key Laboratory of Neurology,Hebei Medical University,Ministry of Education,China,No.2023001(to JC).
文摘N^(6)-methyladenosine RNA methylation,an essential post-transcriptional modification,dynamically regulates RNA metabolism and plays a crucial role in neuronal function.Growing evidence suggests that dysregulated N^(6)-methyladenosine modification contributes to the pathogenesis of neurodegenerative diseases,including Alzheimer’s disease,Parkinson’s disease,multiple sclerosis,and amyotrophic lateral sclerosis.However,the precise mechanisms by which N^(6)-methyladenosine modification influences these conditions remain unclear.This review summarizes the role of m6A modification and its associated regulators in neurodegeneration,focusing on their involvement in key pathological processes.In Alzheimer’s disease,m6A modification contributes to synaptic dysfunction,mitochondrial damage,and neuronal apoptosis.Evidence from APP/PS1,5xFAD,tau transgenic,and Drosophila models demonstrates that regulators such as methyltransferase-like 3 and fat mass and obesity-associated protein influence Alzheimer’s disease progression through neuroinflammation,circular RNAs dysregulation,and autophagy-related mechanisms.In Parkinson’s disease,altered N^(6)-methyladenosine regulator expression affects dopaminergic neuron survival and stress responses by modulating mRNA stability and autophagy-related lncRNAs.In multiple sclerosis and amyotrophic lateral sclerosis,N^(6)-methyladenosine affects immune activation,myelin repair,and the regulation of disease-associated genes such as TDP-43.Beyond N^(6)-methyladenosine,other RNA methylation modifications-such as m1A,m5C,m7G,uracil,and pseudouridine-are implicated in neurodegenerative diseases through their regulation of mitochondrial function,RNA metabolism,and neuronal stress responses.Additionally,N^(6)-methyladenosine exhibits cell type-specific functions:in microglia,it regulates inflammatory activation and phagocytic function;in astrocytes,it modulates metabolic homeostasis and glutamate-associated neurotoxicity;in neurons,it affects synaptic function and neurodegeneration-related gene expression;and in adult neural stem cells,it controls differentiation,neurogenesis,and cognitive plasticity.Recently,several small-molecule inhibitors targeting methyltransferase-like 3 or fat mass and obesity-associated protein have been developed to modulate N^(6)-methyladenosine modification,providing new opportunities for disease intervention,with the targeting of N⁶-methyladenosine-related pathways emerging as a promising therapeutic strategy.However,challenges persist in optimizing the specificity and delivery of these therapeutic approaches.
