Amyotrophic lateral sclerosis is a very disabling disease due to the degeneration of motor neurons.Symptoms include muscle weakness and atrophy,spasticity,and progressive paralysis.Currently,there is no treatment to r...Amyotrophic lateral sclerosis is a very disabling disease due to the degeneration of motor neurons.Symptoms include muscle weakness and atrophy,spasticity,and progressive paralysis.Currently,there is no treatment to reverse damage to motor neurons and cure amyotrophic lateral sclerosis.The only two treatments actually approved,riluzole and edaravone,have shown mitigated beneficial effects.The difficulty to find a cure lies in the complexity and multifaceted pattern of amyotrophic lateral sclerosis pathogenesis.Among mechanisms,abnormal RNA metabolism,nucleocytoplasmic transport defects,accumulation of unfolded protein,and mitochondrial dysfunction would in fine induce oxidative damage and vice versa.A potent therapeutic strategy will be to find molecules that break this vicious circle.Sharpening the nuclear factor erythroid-2 related factor 2 signaling may fulfill this objective since nuclear factor erythroid-2 related factor 2 has a multitarget profile controlling antioxidant defense,mitochondrial functioning,and inflammation.We here discuss the interest of developing nuclear factor erythroid-2 related factor 2-based therapy in regard to the pathophysiological mechanisms and we provide a general overview of the attempted clinical assays in amyotrophic lateral sclerosis.展开更多
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
Initially,the Sigma-1 receptor(S1R)was incorrectly categorized as one of the opioid receptors.But it has since become clear that S1R is a non-opioid non-phencyclidine receptor with molecular chaperone activity.S1R is ...Initially,the Sigma-1 receptor(S1R)was incorrectly categorized as one of the opioid receptors.But it has since become clear that S1R is a non-opioid non-phencyclidine receptor with molecular chaperone activity.S1R is a 223 amino-acid long protein that shares no clear homology with any other known mammalian proteins,its closest homolog being the fungal ERG2 sterol isomerase.Even its pharmacological counterpart,the Sigma-2 receptor that was only recently cloned,is genetically distinct.S1R is more likely considered as an atypical ligand-modulated chaperone protein.S1R is widely expressed in many organs including brain where its function has mainly been explored.展开更多
基金supported by a grant from the Association Française contre les Myopathies(AFM Téléthongrant 23667,to JCL).
文摘Amyotrophic lateral sclerosis is a very disabling disease due to the degeneration of motor neurons.Symptoms include muscle weakness and atrophy,spasticity,and progressive paralysis.Currently,there is no treatment to reverse damage to motor neurons and cure amyotrophic lateral sclerosis.The only two treatments actually approved,riluzole and edaravone,have shown mitigated beneficial effects.The difficulty to find a cure lies in the complexity and multifaceted pattern of amyotrophic lateral sclerosis pathogenesis.Among mechanisms,abnormal RNA metabolism,nucleocytoplasmic transport defects,accumulation of unfolded protein,and mitochondrial dysfunction would in fine induce oxidative damage and vice versa.A potent therapeutic strategy will be to find molecules that break this vicious circle.Sharpening the nuclear factor erythroid-2 related factor 2 signaling may fulfill this objective since nuclear factor erythroid-2 related factor 2 has a multitarget profile controlling antioxidant defense,mitochondrial functioning,and inflammation.We here discuss the interest of developing nuclear factor erythroid-2 related factor 2-based therapy in regard to the pathophysiological mechanisms and we provide a general overview of the attempted clinical assays in amyotrophic lateral sclerosis.
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Initially,the Sigma-1 receptor(S1R)was incorrectly categorized as one of the opioid receptors.But it has since become clear that S1R is a non-opioid non-phencyclidine receptor with molecular chaperone activity.S1R is a 223 amino-acid long protein that shares no clear homology with any other known mammalian proteins,its closest homolog being the fungal ERG2 sterol isomerase.Even its pharmacological counterpart,the Sigma-2 receptor that was only recently cloned,is genetically distinct.S1R is more likely considered as an atypical ligand-modulated chaperone protein.S1R is widely expressed in many organs including brain where its function has mainly been explored.
