Growing evidence suggests that abnormal lipid metabolism occurs in amyotrophic lateral sclerosis,even in the presymptomatic stage,implying an etiologic link.However,the genetic mechanism underlying altered lipid level...Growing evidence suggests that abnormal lipid metabolism occurs in amyotrophic lateral sclerosis,even in the presymptomatic stage,implying an etiologic link.However,the genetic mechanism underlying altered lipid levels in amyotrophic lateral sclerosis remains elusive.Therefore,in this study,we performed genetic correlation analysis,a cross-trait meta-analysis,tissue-specific enrichment analysis,and bidirectional two-sample Mendelian randomization analysis of European population to explore whether there is a genetic and causal relationship between lipids and amyotrophic lateral sclerosis.The effect of lipid-lowering drugs on amyotrophic lateral sclerosis was also evaluated using a drug target Mendelian randomization approach.The results showed a positive genetic correlation between amyotrophic lateral sclerosis and both high-density lipoprotein cholesterol and apolipoprotein A1 and identified 71 independent shared loci between amyotrophic lateral sclerosis and high-density lipoprotein cholesterol,as well as 55 independent shared loci between amyotrophic lateral sclerosis and apolipoprotein A1.These shared loci were enriched in the lipid metabolic pathway and the alcohol metabolic pathway.Further Mendelian randomization analysis targeting lipid-lowering drugs showed that single nucleotide polymorphisms within the ACLY and PCSK9 genes had a protective effect against amyotrophic lateral sclerosis risk by decreasing low-density lipoprotein cholesterol.The combination of ACLY and PCSK9 inhibitors has a greater protective effect on amyotrophic lateral sclerosis risk than that of PCSK9 inhibitors alone.In summary,there is a common genetic structure between lipids and amyotrophic lateral sclerosis.Mendelian randomization analysis supports an association between elevated blood lipids and the risk of developing amyotrophic lateral sclerosis,and the use of ACLY or PCSK9 inhibitors may improve disease prognosis.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
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
Amyotrophic lateral sclerosis(ALS)is a fatal,late-onset neurodegenerative disorder characterized by the progressive degeneration of motor neurons in the motor cortex,brainstem,and spinal cord(Feldman et al.,2022).
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
Amyotrophic lateral sclerosis(ALS)is a rapidly progressing neurodegenerative disease,leading to muscle weakness,paralysis and ultimately death due to respiratory failure.Currently licensed drugs have only very limited...Amyotrophic lateral sclerosis(ALS)is a rapidly progressing neurodegenerative disease,leading to muscle weakness,paralysis and ultimately death due to respiratory failure.Currently licensed drugs have only very limited effects on slowing down disease progression or biomarkers.Despite numerous successful preclinical analyses,most new drugs fail when translated to clinical trials(Petrov et al.,2017).This is believed to be,in part,due to the multilayer heterogeneity of ALS(e.g.,clinical,genetic,and molecular;Tzeplaeff et al.,2024).Studies integrating multi-omic data are still limited,making it difficult to fully understand the biological complexity that characterizes the disease.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
Amyotrophic lateral sclerosis is a devastating neurodegenerative disease marked by progressive motor neuron degeneration.Despite extensive research,effective treatments remain elusive,underscoring the need to explore ...Amyotrophic lateral sclerosis is a devastating neurodegenerative disease marked by progressive motor neuron degeneration.Despite extensive research,effective treatments remain elusive,underscoring the need to explore the molecular mechanisms driving disease progression.The amyotrophic lateral sclerosis complexity is further compounded by its large heterogeneity,encompassing both genetic and sporadic forms,diverse phenotypic presentations,and highly variable progression rates.A key pathological feature of amyotrophic lateral sclerosis is the aggregation of TAR DNA-binding protein 43,which contributes to cellular toxicity,neuroinflammation,and neuronal dysfunction.This review explores the complex interplay between TAR DNA-binding protein 43 pathology,immunity dysregulation,and the gut-brain axis,with a focus on the role of microbiome-derived metabolites in amyotrophic lateral sclerosis.Neuroinflammation,mediated by both innate and adaptive immunity,plays a central role in disease pathogenesis,with TAR DNA-binding protein 43 influencing immune signaling and exacerbating neurotoxicity.Additionally,disruptions in gut microbiota composition and intestinal barrier integrity,frequently observed in amyotrophic lateral sclerosis patients,suggest a potential role for the gut-brain axis in modulating neurodegenerative processes.By integrating evidence from emerging studies,our aim is to clarify how TAR DNA-binding protein 43 aggregation contributes to neuroinflammation and immune dysfunction while exploring the gut microbiota role as both a modulator and potential biomarker of disease.Understanding these interactions could pave the way for novel therapeutic strategies,including microbiome-targeted interventions such as probiotics,dietary modifications,or immune-modulating therapies.Finally,unraveling the TAR DNA-binding protein 43-immune system-microbiome axis may offer new avenues for personalized treatments aimed at mitigating neuroinflammation,slowing amyotrophic lateral sclerosis progression,and improving patient outcomes and life quality.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
Objective Adaptive immune responses play a critical role in the pathogenesis of amyotrophic lateral sclerosis(ALS).In this study,we investigated the functional mechanisms of T cell subtypes and assessed the causal lin...Objective Adaptive immune responses play a critical role in the pathogenesis of amyotrophic lateral sclerosis(ALS).In this study,we investigated the functional mechanisms of T cell subtypes and assessed the causal links between CD4+cytotoxic T cell-related genes and ALS risk.Methods Single-cell RNA sequencing(scRNA-seq)of peripheral blood mononuclear cells(PBMCs)from patients with ALS and healthy controls(HC)was used to identify differentially expressed genes(DEGs)in CD4+cytotoxic T cells.Comprehensive analyses of CD4+cytotoxic T cells,including pseudotemporal trajectory,intercellular communication,and metabolic pathway analysis,were performed.Mendelian randomization(MR)analysis evaluated the causal effects of DEGs on ALS risk,with validation using independent genome-wide association study(GWAS)data.Expression patterns of the causal genes were further verified using scRNA-seq,bulk-seq,and clinical samples.Results CD4+cytotoxic T cells were significantly expanded in patients with ALS.The upregulated genes S100A6,SERPINB6,SMAD7,and TPST2 were positively correlated with ALS susceptibility,whereas DIP2A showed a protective association.Conclusion S100A6,SERPINB6,SMAD7,TPST2,and DIP2A were identified as causal genes and potential therapeutic targets in ALS,implicating CD4+cytotoxic T cells in the disease mechanisms.Further studies targeting these genes and neuroinflammatory pathways are warranted.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
基金funded by the National Natural Science Foundation of China,Nos.82401670(to KX),81873784(to DF),and 82071426(to DF)the Clinical Cohort Construction Program of Peking University Third Hospital,No.BYSYDL2019002(to DF)the Postdoctoral Fellowship Program of China Postdoctoral Science Foundation,No.GZC20230152(to KX).
文摘Growing evidence suggests that abnormal lipid metabolism occurs in amyotrophic lateral sclerosis,even in the presymptomatic stage,implying an etiologic link.However,the genetic mechanism underlying altered lipid levels in amyotrophic lateral sclerosis remains elusive.Therefore,in this study,we performed genetic correlation analysis,a cross-trait meta-analysis,tissue-specific enrichment analysis,and bidirectional two-sample Mendelian randomization analysis of European population to explore whether there is a genetic and causal relationship between lipids and amyotrophic lateral sclerosis.The effect of lipid-lowering drugs on amyotrophic lateral sclerosis was also evaluated using a drug target Mendelian randomization approach.The results showed a positive genetic correlation between amyotrophic lateral sclerosis and both high-density lipoprotein cholesterol and apolipoprotein A1 and identified 71 independent shared loci between amyotrophic lateral sclerosis and high-density lipoprotein cholesterol,as well as 55 independent shared loci between amyotrophic lateral sclerosis and apolipoprotein A1.These shared loci were enriched in the lipid metabolic pathway and the alcohol metabolic pathway.Further Mendelian randomization analysis targeting lipid-lowering drugs showed that single nucleotide polymorphisms within the ACLY and PCSK9 genes had a protective effect against amyotrophic lateral sclerosis risk by decreasing low-density lipoprotein cholesterol.The combination of ACLY and PCSK9 inhibitors has a greater protective effect on amyotrophic lateral sclerosis risk than that of PCSK9 inhibitors alone.In summary,there is a common genetic structure between lipids and amyotrophic lateral sclerosis.Mendelian randomization analysis supports an association between elevated blood lipids and the risk of developing amyotrophic lateral sclerosis,and the use of ACLY or PCSK9 inhibitors may improve disease prognosis.
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 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 Else Kröner-Fresenius-Stiftung(2021-EKSE.95)the Deutsche Forschungsgemeinschaft(CRC1678 and Germany’s Excellence Strategy-CECAD,EXC 2030-390661388)(to DV).
文摘Amyotrophic lateral sclerosis(ALS)is a fatal,late-onset neurodegenerative disorder characterized by the progressive degeneration of motor neurons in the motor cortex,brainstem,and spinal cord(Feldman et al.,2022).
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.
文摘Amyotrophic lateral sclerosis(ALS)is a rapidly progressing neurodegenerative disease,leading to muscle weakness,paralysis and ultimately death due to respiratory failure.Currently licensed drugs have only very limited effects on slowing down disease progression or biomarkers.Despite numerous successful preclinical analyses,most new drugs fail when translated to clinical trials(Petrov et al.,2017).This is believed to be,in part,due to the multilayer heterogeneity of ALS(e.g.,clinical,genetic,and molecular;Tzeplaeff et al.,2024).Studies integrating multi-omic data are still limited,making it difficult to fully understand the biological complexity that characterizes the disease.
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.
文摘Amyotrophic lateral sclerosis is a devastating neurodegenerative disease marked by progressive motor neuron degeneration.Despite extensive research,effective treatments remain elusive,underscoring the need to explore the molecular mechanisms driving disease progression.The amyotrophic lateral sclerosis complexity is further compounded by its large heterogeneity,encompassing both genetic and sporadic forms,diverse phenotypic presentations,and highly variable progression rates.A key pathological feature of amyotrophic lateral sclerosis is the aggregation of TAR DNA-binding protein 43,which contributes to cellular toxicity,neuroinflammation,and neuronal dysfunction.This review explores the complex interplay between TAR DNA-binding protein 43 pathology,immunity dysregulation,and the gut-brain axis,with a focus on the role of microbiome-derived metabolites in amyotrophic lateral sclerosis.Neuroinflammation,mediated by both innate and adaptive immunity,plays a central role in disease pathogenesis,with TAR DNA-binding protein 43 influencing immune signaling and exacerbating neurotoxicity.Additionally,disruptions in gut microbiota composition and intestinal barrier integrity,frequently observed in amyotrophic lateral sclerosis patients,suggest a potential role for the gut-brain axis in modulating neurodegenerative processes.By integrating evidence from emerging studies,our aim is to clarify how TAR DNA-binding protein 43 aggregation contributes to neuroinflammation and immune dysfunction while exploring the gut microbiota role as both a modulator and potential biomarker of disease.Understanding these interactions could pave the way for novel therapeutic strategies,including microbiome-targeted interventions such as probiotics,dietary modifications,or immune-modulating therapies.Finally,unraveling the TAR DNA-binding protein 43-immune system-microbiome axis may offer new avenues for personalized treatments aimed at mitigating neuroinflammation,slowing amyotrophic lateral sclerosis progression,and improving patient outcomes and life quality.
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).
文摘Objective Adaptive immune responses play a critical role in the pathogenesis of amyotrophic lateral sclerosis(ALS).In this study,we investigated the functional mechanisms of T cell subtypes and assessed the causal links between CD4+cytotoxic T cell-related genes and ALS risk.Methods Single-cell RNA sequencing(scRNA-seq)of peripheral blood mononuclear cells(PBMCs)from patients with ALS and healthy controls(HC)was used to identify differentially expressed genes(DEGs)in CD4+cytotoxic T cells.Comprehensive analyses of CD4+cytotoxic T cells,including pseudotemporal trajectory,intercellular communication,and metabolic pathway analysis,were performed.Mendelian randomization(MR)analysis evaluated the causal effects of DEGs on ALS risk,with validation using independent genome-wide association study(GWAS)data.Expression patterns of the causal genes were further verified using scRNA-seq,bulk-seq,and clinical samples.Results CD4+cytotoxic T cells were significantly expanded in patients with ALS.The upregulated genes S100A6,SERPINB6,SMAD7,and TPST2 were positively correlated with ALS susceptibility,whereas DIP2A showed a protective association.Conclusion S100A6,SERPINB6,SMAD7,TPST2,and DIP2A were identified as causal genes and potential therapeutic targets in ALS,implicating CD4+cytotoxic T cells in the disease mechanisms.Further studies targeting these genes and neuroinflammatory pathways are warranted.
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.
