Amyotrophic lateral sclerosis(ALS)is a devastating neurodegenerative disorder characterized by loss of upper and lower motor neurons.Different mechanisms contribute to the disease initiation and progression,includin...Amyotrophic lateral sclerosis(ALS)is a devastating neurodegenerative disorder characterized by loss of upper and lower motor neurons.Different mechanisms contribute to the disease initiation and progression,including mitochondrial dysfunction which has been proposed to be a central determinant in ALS pathogenesis.Indeed,while mitochondrial defects have been mainly described in ALS-linked SOD1 mutants,it is now well established that mitochondria become also dysfunctional in other ALS conditions.In such context,the mitochondrial quality control system allows to restore normal functioning of mitochondria and to prevent cell death,by both eliminating and replacing damaged mitochondrial components or by degrading the entire organelle through mitophagy.Recent evidence shows that ALS-related genes interfere with the mitochondrial quality control system.This review highlights how ineffective mitochondrial quality control may render motor neurons defenseless towards the accumulating mitochondrial damage in ALS.展开更多
Amyotrophic lateral sclerosis(ALS)is a neuromuscular condition resulting from the progressive degeneration of motor neurons in the cortex,brainstem,and spinal cord.While the typical clinical phenotype of ALS involves ...Amyotrophic lateral sclerosis(ALS)is a neuromuscular condition resulting from the progressive degeneration of motor neurons in the cortex,brainstem,and spinal cord.While the typical clinical phenotype of ALS involves both upper and lower motor neurons,human and animal studies over the years have highlighted the potential spread to other motor and non-motor regions,expanding the phenotype of ALS.Although superoxide dismutase 1(SOD1)mutations represent a minority of ALS cases,the SOD1 gene remains a milestone in ALS research as it represents the first genetic target for personalized therapies.Despite numerous single case reports or case series exhibiting extramotor symptoms in patients with ALS mutations in SOD1(SOD1-ALS),no studies have comprehensively explored the full spectrum of extramotor neurological manifestations in this subpopulation.In this narrative review,we analyze and discuss the available literature on extrapyramidal and non-motor features during SOD1-ALS.The multifaceted expression of SOD1 could deepen our understanding of the pathogenic mechanisms,pointing towards a multidisciplinary approach for affected patients in light of new therapeutic strategies for SOD1-ALS.展开更多
Amyotrophic lateral sclerosis (ALS) is a fatal progressive disorder characterized by the selective degeneration of motor neurons (MN). The impact of peripheral immune status on disease progression and MN survival ...Amyotrophic lateral sclerosis (ALS) is a fatal progressive disorder characterized by the selective degeneration of motor neurons (MN). The impact of peripheral immune status on disease progression and MN survival is becoming increasingly recognized in the ALS research field. In this review, we briefly discuss findings from mouse models of peripheral nerve injury and immunodeficiency to understand how the immune system regulates MN survival. We extend these observations to similar studies in the widely used superoxide dismutase 1 (SOD1) mouse model of ALS. Last, we present future hypotheses to identify potential causative factors that lead to immune dysregulation in ALS. The lessons from preceding work in this area offer new exciting directions to bridge the gap in our current understanding of immune mediated neuroprotection in ALS.展开更多
文摘Amyotrophic lateral sclerosis(ALS)is a devastating neurodegenerative disorder characterized by loss of upper and lower motor neurons.Different mechanisms contribute to the disease initiation and progression,including mitochondrial dysfunction which has been proposed to be a central determinant in ALS pathogenesis.Indeed,while mitochondrial defects have been mainly described in ALS-linked SOD1 mutants,it is now well established that mitochondria become also dysfunctional in other ALS conditions.In such context,the mitochondrial quality control system allows to restore normal functioning of mitochondria and to prevent cell death,by both eliminating and replacing damaged mitochondrial components or by degrading the entire organelle through mitophagy.Recent evidence shows that ALS-related genes interfere with the mitochondrial quality control system.This review highlights how ineffective mitochondrial quality control may render motor neurons defenseless towards the accumulating mitochondrial damage in ALS.
文摘Amyotrophic lateral sclerosis(ALS)is a neuromuscular condition resulting from the progressive degeneration of motor neurons in the cortex,brainstem,and spinal cord.While the typical clinical phenotype of ALS involves both upper and lower motor neurons,human and animal studies over the years have highlighted the potential spread to other motor and non-motor regions,expanding the phenotype of ALS.Although superoxide dismutase 1(SOD1)mutations represent a minority of ALS cases,the SOD1 gene remains a milestone in ALS research as it represents the first genetic target for personalized therapies.Despite numerous single case reports or case series exhibiting extramotor symptoms in patients with ALS mutations in SOD1(SOD1-ALS),no studies have comprehensively explored the full spectrum of extramotor neurological manifestations in this subpopulation.In this narrative review,we analyze and discuss the available literature on extrapyramidal and non-motor features during SOD1-ALS.The multifaceted expression of SOD1 could deepen our understanding of the pathogenic mechanisms,pointing towards a multidisciplinary approach for affected patients in light of new therapeutic strategies for SOD1-ALS.
基金supported by grants from NIH/NINDS R01 funding NS40433
文摘Amyotrophic lateral sclerosis (ALS) is a fatal progressive disorder characterized by the selective degeneration of motor neurons (MN). The impact of peripheral immune status on disease progression and MN survival is becoming increasingly recognized in the ALS research field. In this review, we briefly discuss findings from mouse models of peripheral nerve injury and immunodeficiency to understand how the immune system regulates MN survival. We extend these observations to similar studies in the widely used superoxide dismutase 1 (SOD1) mouse model of ALS. Last, we present future hypotheses to identify potential causative factors that lead to immune dysregulation in ALS. The lessons from preceding work in this area offer new exciting directions to bridge the gap in our current understanding of immune mediated neuroprotection in ALS.