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
TDP43 pathology is seen in a large majority of amyotrophic lateral sclerosis(ALS)cases,suggesting a central pathogenic role of this regulatory protein.Clarifying the molecular mechanism controlling TDP43 stability and...TDP43 pathology is seen in a large majority of amyotrophic lateral sclerosis(ALS)cases,suggesting a central pathogenic role of this regulatory protein.Clarifying the molecular mechanism controlling TDP43 stability and subcellular location might provide important insights into ALS therapy.The ubiquitin E3 ligase RNF220 is involved in different neural developmental processes through various molecular targets in the mouse.Here,we report that the RNF2207 mice showed progressively decreasing mobility to different extents,some of which developed typical ALS pathological characteristics in spinal motor neurons,including TDP43 cytoplasmic accumulation,atrocytosis,muscle denervation,and atrophy.Mechanistically,RNF220 interacts with TDP43 in vitro and in vivo and promotes its polyubiquitination and proteasomal degradation.In conclusion,we propose that RNF220 might be a modifier of TDP43 function in vivo and contribute to TDP43 pathology in neurodegenerative disease like ALS.展开更多
Primary age-related tauopathy(PART)is characterized by the presence of tau neurofibrillary tangles(NFTs)which are typically observed in Alzheimer’s disease(AD)brains,with few or withoutβ-amyloid(Aβ)plaques.The diag...Primary age-related tauopathy(PART)is characterized by the presence of tau neurofibrillary tangles(NFTs)which are typically observed in Alzheimer’s disease(AD)brains,with few or withoutβ-amyloid(Aβ)plaques.The diagnosis of PART can be categorized into“definite”or“possible”depending on the amount of Aβplaques.Definite PART is diagnosed when NFTs are observed and the Braak stage is≤IV,with Thal AβPhase 0(Crary et al.,2014).According to the neuropathological diagnostic criteria,we reported reported that PART was frequently observed in the Chinese population according to our findings from specimens in our brain bank,with 47%of brain bank subjects meeting the criteria for PART.There is no consensus on the nature of PART.It remains to be elucidated whether PART is an early form of AD or a novel tauopathy(Duyckaerts et al.,2015;Jellinger et al.,2015).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.
基金This work was supported by the National Natural Science Foundation of China(31671521 and 31871483 to B.M.)Yunnan Basic Research Program(202001AS070036 to B.M.).
文摘TDP43 pathology is seen in a large majority of amyotrophic lateral sclerosis(ALS)cases,suggesting a central pathogenic role of this regulatory protein.Clarifying the molecular mechanism controlling TDP43 stability and subcellular location might provide important insights into ALS therapy.The ubiquitin E3 ligase RNF220 is involved in different neural developmental processes through various molecular targets in the mouse.Here,we report that the RNF2207 mice showed progressively decreasing mobility to different extents,some of which developed typical ALS pathological characteristics in spinal motor neurons,including TDP43 cytoplasmic accumulation,atrocytosis,muscle denervation,and atrophy.Mechanistically,RNF220 interacts with TDP43 in vitro and in vivo and promotes its polyubiquitination and proteasomal degradation.In conclusion,we propose that RNF220 might be a modifier of TDP43 function in vivo and contribute to TDP43 pathology in neurodegenerative disease like ALS.
基金Project supported by the National Natural Science Foundation of China(Nos.91632109 and 81971184)the Zhejiang Provincial Natural Science Foundation of China(No.LY16H090013)the Zhejiang Medical and Health Science and Technology Plan Project(No.WKJ2013-2-009),China.
文摘Primary age-related tauopathy(PART)is characterized by the presence of tau neurofibrillary tangles(NFTs)which are typically observed in Alzheimer’s disease(AD)brains,with few or withoutβ-amyloid(Aβ)plaques.The diagnosis of PART can be categorized into“definite”or“possible”depending on the amount of Aβplaques.Definite PART is diagnosed when NFTs are observed and the Braak stage is≤IV,with Thal AβPhase 0(Crary et al.,2014).According to the neuropathological diagnostic criteria,we reported reported that PART was frequently observed in the Chinese population according to our findings from specimens in our brain bank,with 47%of brain bank subjects meeting the criteria for PART.There is no consensus on the nature of PART.It remains to be elucidated whether PART is an early form of AD or a novel tauopathy(Duyckaerts et al.,2015;Jellinger et al.,2015).
