Amyotrophic lateral syndrome(ALS)is a progressive degenerative disorder characterized by motor neuron death and axon degeneration.Mitochondrial dysfunction plays a key role in the pathogenesis of ALS,the mechanism of ...Amyotrophic lateral syndrome(ALS)is a progressive degenerative disorder characterized by motor neuron death and axon degeneration.Mitochondrial dysfunction plays a key role in the pathogenesis of ALS,the mechanism of which remains poorly understood.The B-cell lymphoma-2(Bcl-2)family of proteins that control and mediate mitochondrial function and apoptosis,including the pro-apoptotic members Bcl2-Associated X(Bax),are involved in ALS development.The death receptor 6(DR6)regulates motor neuron death in ALS,and DR6 antibodies can prevent axon degeneration and motor neuron damage by blocking DR6.Previous studies demonstrated that PSAP localized to mitochondria and was required for DR6-induced apoptosis.In this study,SOD1^(G93A) was transfected into the motor neuron cell line NSC-34 to serve as an ALS cell model in vitro.The data assessed the role of PSAP in SOD1^(G93A)induced apoptosis and demonstrated that the overexpression of SOD1^(G93A),but not wtSOD1,induced PARP cleavage,caspase-3 activation,cytochrome c release,and Bax translocation.PSAP,Bax,and Bak were necessary for SOD1^(G93A)induced apoptosis,as silencing PSAP inhibited SOD1^(G93A)-mediated cell death that was dependent on Bax-Bak interaction.展开更多
Previous studies have confirmed that the beclin 1 complex plays a key role in the initial stage of autophagy and deregulated autophagy might involve in amyotrophic lateral sclerosis. However, the mechanism underlying ...Previous studies have confirmed that the beclin 1 complex plays a key role in the initial stage of autophagy and deregulated autophagy might involve in amyotrophic lateral sclerosis. However, the mechanism underlying altered autophagy associated with the beclin 1 complex remains un- clear. In this study, we transfected the Cu/Zn superoxide dismutase 1 G93A mutant protein into the motor neuron-like cell line NSC34 cultured in vitro. Western blotting and co-immunopre- cipitation showed that the Cu/Zn superoxide dismutase 1 G93A mutant enhanced the turnover of autophagic marker microtubule-associated protein light chain 3II （LC3Ⅱ） and stimulated the conversion of EGFP-LC3Ⅰ to EGFP-LC3Ⅱ, but had little influence on the binding capacity of the autophagy modulators ATG14L, rubicon, UVRAG, and hVps34 to beclin 1 during auto- phagosome formation. These results suggest that the amyotrophic lateral sclerosis-linked Cu/Zn superoxide dismutase I G93A mutant can upregulate autophagic activity in NSC34 cells, but that this does not markedly affect beclin 1 complex components.展开更多
Amyotrophic lateral sclerosis is a fatal multisystemic neurodegenerative disease with motor neurons being a primary target.Although progressive weakness is a hallmark feature of amyotrophic lateral sclerosis,there is ...Amyotrophic lateral sclerosis is a fatal multisystemic neurodegenerative disease with motor neurons being a primary target.Although progressive weakness is a hallmark feature of amyotrophic lateral sclerosis,there is considerable heterogeneity,including clinical presentation,progression,and the underlying triggers for disease initiation.Based on longitudinal studies with families harboring amyotrophic lateral sclerosis-associated gene mutations,it has become apparent that overt disease is preceded by a prodromal phase,possibly in years,where compensatory mechanisms delay symptom onset.Since 85-90%of amyotrophic lateral sclerosis is sporadic,there is a strong need for identifying biomarkers that can detect this prodromal phase as motor neurons have limited capacity for regeneration.Current Food and Drug Administration-approved therapies work by slowing the degenerative process and are most effective early in the disease.Skeletal muscle,including the neuromuscular junction,manifests abnormalities at the earliest stages of the disease,before motor neuron loss,making it a promising source for identifying biomarkers of the prodromal phase.The accessibility of muscle through biopsy provides a lens into the distal motor system at earlier stages and in real time.The advent of“omics”technology has led to the identification of numerous dysregulated molecules in amyotrophic lateral sclerosis muscle,ranging from coding and non-coding RNAs to proteins and metabolites.This technology has opened the door for identifying biomarkers of disease activity and providing insight into disease mechanisms.A major challenge is correlating the myriad of dysregulated molecules with clinical or histological progression and understanding their relevance to presymptomatic phases of disease.There are two major goals of this review.The first is to summarize some of the biomarkers identified in human amyotrophic lateral sclerosis muscle that have a clinicopathological correlation with disease activity,evidence of a similar dysregulation in the SOD1G93A mouse during presymptomatic stages,and evidence of progressive change during disease progression.The second goal is to review the molecular pathways these biomarkers reflect and their potential role in mitigating or promoting disease progression,and as such,their potential as therapeutic targets in amyotrophic lateral sclerosis.展开更多
基金supported by grants from the National Natural Science Foundation of China[Grant No.81701076,Linlin Zeng]the Science and Technology Department of Jilin Province[Grant No.20190701037GH,Fuqiang Zhang+2 种基金Grant No.20190701036GH,Linlin Zengand Grant No.20200201386JC,Guodong Li]the Education Department of Jilin Province[Grant No.JJKH20200948KJ,Linlin Zeng]。
文摘Amyotrophic lateral syndrome(ALS)is a progressive degenerative disorder characterized by motor neuron death and axon degeneration.Mitochondrial dysfunction plays a key role in the pathogenesis of ALS,the mechanism of which remains poorly understood.The B-cell lymphoma-2(Bcl-2)family of proteins that control and mediate mitochondrial function and apoptosis,including the pro-apoptotic members Bcl2-Associated X(Bax),are involved in ALS development.The death receptor 6(DR6)regulates motor neuron death in ALS,and DR6 antibodies can prevent axon degeneration and motor neuron damage by blocking DR6.Previous studies demonstrated that PSAP localized to mitochondria and was required for DR6-induced apoptosis.In this study,SOD1^(G93A) was transfected into the motor neuron cell line NSC-34 to serve as an ALS cell model in vitro.The data assessed the role of PSAP in SOD1^(G93A)induced apoptosis and demonstrated that the overexpression of SOD1^(G93A),but not wtSOD1,induced PARP cleavage,caspase-3 activation,cytochrome c release,and Bax translocation.PSAP,Bax,and Bak were necessary for SOD1^(G93A)induced apoptosis,as silencing PSAP inhibited SOD1^(G93A)-mediated cell death that was dependent on Bax-Bak interaction.
基金supported in part by an Oversea Study Fellowship from the China Scholarship Council,No.2008630089
文摘Previous studies have confirmed that the beclin 1 complex plays a key role in the initial stage of autophagy and deregulated autophagy might involve in amyotrophic lateral sclerosis. However, the mechanism underlying altered autophagy associated with the beclin 1 complex remains un- clear. In this study, we transfected the Cu/Zn superoxide dismutase 1 G93A mutant protein into the motor neuron-like cell line NSC34 cultured in vitro. Western blotting and co-immunopre- cipitation showed that the Cu/Zn superoxide dismutase 1 G93A mutant enhanced the turnover of autophagic marker microtubule-associated protein light chain 3II （LC3Ⅱ） and stimulated the conversion of EGFP-LC3Ⅰ to EGFP-LC3Ⅱ, but had little influence on the binding capacity of the autophagy modulators ATG14L, rubicon, UVRAG, and hVps34 to beclin 1 during auto- phagosome formation. These results suggest that the amyotrophic lateral sclerosis-linked Cu/Zn superoxide dismutase I G93A mutant can upregulate autophagic activity in NSC34 cells, but that this does not markedly affect beclin 1 complex components.
基金supported by NIH Grants R01NS092651 and R21NS111275-01the Department of Veterans Affairs,BX001148 and BX005899(to PHK)。
文摘Amyotrophic lateral sclerosis is a fatal multisystemic neurodegenerative disease with motor neurons being a primary target.Although progressive weakness is a hallmark feature of amyotrophic lateral sclerosis,there is considerable heterogeneity,including clinical presentation,progression,and the underlying triggers for disease initiation.Based on longitudinal studies with families harboring amyotrophic lateral sclerosis-associated gene mutations,it has become apparent that overt disease is preceded by a prodromal phase,possibly in years,where compensatory mechanisms delay symptom onset.Since 85-90%of amyotrophic lateral sclerosis is sporadic,there is a strong need for identifying biomarkers that can detect this prodromal phase as motor neurons have limited capacity for regeneration.Current Food and Drug Administration-approved therapies work by slowing the degenerative process and are most effective early in the disease.Skeletal muscle,including the neuromuscular junction,manifests abnormalities at the earliest stages of the disease,before motor neuron loss,making it a promising source for identifying biomarkers of the prodromal phase.The accessibility of muscle through biopsy provides a lens into the distal motor system at earlier stages and in real time.The advent of“omics”technology has led to the identification of numerous dysregulated molecules in amyotrophic lateral sclerosis muscle,ranging from coding and non-coding RNAs to proteins and metabolites.This technology has opened the door for identifying biomarkers of disease activity and providing insight into disease mechanisms.A major challenge is correlating the myriad of dysregulated molecules with clinical or histological progression and understanding their relevance to presymptomatic phases of disease.There are two major goals of this review.The first is to summarize some of the biomarkers identified in human amyotrophic lateral sclerosis muscle that have a clinicopathological correlation with disease activity,evidence of a similar dysregulation in the SOD1G93A mouse during presymptomatic stages,and evidence of progressive change during disease progression.The second goal is to review the molecular pathways these biomarkers reflect and their potential role in mitigating or promoting disease progression,and as such,their potential as therapeutic targets in amyotrophic lateral sclerosis.
