The onset of amyotrophic lateral sclerosis is usually characterized by focal death of both upper and/or lower motor neurons occurring in the motor cortex,basal ganglia,brainstem,and spinal cord,and commonly involves t...The onset of amyotrophic lateral sclerosis is usually characterized by focal death of both upper and/or lower motor neurons occurring in the motor cortex,basal ganglia,brainstem,and spinal cord,and commonly involves the muscles of the upper and/or lower extremities,and the muscles of the bulbar and/or respiratory regions.However,as the disease progresses,it affects the adjacent body regions,leading to generalized muscle weakness,occasionally along with memory,cognitive,behavioral,and language impairments;respiratory dysfunction occurs at the final stage of the disease.The disease has a complicated pathophysiology and currently,only riluzole,edaravone,and phenylbutyrate/taurursodiol are licensed to treat amyotrophic lateral sclerosis in many industrialized countries.The TAR DNA-binding protein 43 inclusions are observed in 97%of those diagnosed with amyotrophic lateral sclerosis.This review provides a preliminary overview of the potential effects of TAR DNAbinding protein 43 in the pathogenesis of amyotrophic lateral sclerosis,including the abnormalities in nucleoplasmic transport,RNA function,post-translational modification,liquid-liquid phase separation,stress granules,mitochondrial dysfunction,oxidative stress,axonal transport,protein quality control system,and non-cellular autonomous functions(e.g.,glial cell functions and prion-like propagation).展开更多
Enterovirus A71(EV-A71)is one of the etiological pathogens leading to hand,foot,and mouth disease(HFMD),which can cause severe neurological complications.The neuropathogenesis of EV-A71 infection is not well understoo...Enterovirus A71(EV-A71)is one of the etiological pathogens leading to hand,foot,and mouth disease(HFMD),which can cause severe neurological complications.The neuropathogenesis of EV-A71 infection is not well understood.The mislocalization and aggregation of TAR DNA-binding protein 43(TDP-43)is the pathological hallmark of amyotrophic lateral sclerosis(ALS).However,whether TDP-43 was impacted by EV-A71 infection is unknown.This study demonstrated that TDP-43 was cleaved during EV-A71 infection.The cleavage of TDP-43 requires EV-A71 replication rather than the activated caspases due to viral infection.TDP-43 is cleaved by viral protease 3 C between the residues 331 Q and332 S,while mutated TDP-43(Q331 A)was not cleaved.In addition,mutated 3 C which lacks the protease activity failed to induce TDP-43 cleavage.We also found that TDP-43 was translocated from the nucleus to the cytoplasm,and the mislocalization of TDP-43 was induced by viral protease 2 A rather than 3 C.Taken together,we demonstrated that TDP-43 was cleaved by viral protease and translocated to the cytoplasm during EV-A71 infection,implicating the possible involvement of TDP-43 in the pathogenesis of EV-A71 infection.展开更多
基金in part supported by the National Natural Science Foundation of China,Nos.30560042,81160161,81360198,and 82160255Education Department of Jiangxi Province,Nos.GJJ13198 and GJJ170021+1 种基金Jiangxi Provincial Department of Science and Technology,No.20192BAB205043Health and Family Planning Commission of Jiangxi Province,Nos.20181019 and 202210002(all to RX)。
文摘The onset of amyotrophic lateral sclerosis is usually characterized by focal death of both upper and/or lower motor neurons occurring in the motor cortex,basal ganglia,brainstem,and spinal cord,and commonly involves the muscles of the upper and/or lower extremities,and the muscles of the bulbar and/or respiratory regions.However,as the disease progresses,it affects the adjacent body regions,leading to generalized muscle weakness,occasionally along with memory,cognitive,behavioral,and language impairments;respiratory dysfunction occurs at the final stage of the disease.The disease has a complicated pathophysiology and currently,only riluzole,edaravone,and phenylbutyrate/taurursodiol are licensed to treat amyotrophic lateral sclerosis in many industrialized countries.The TAR DNA-binding protein 43 inclusions are observed in 97%of those diagnosed with amyotrophic lateral sclerosis.This review provides a preliminary overview of the potential effects of TAR DNAbinding protein 43 in the pathogenesis of amyotrophic lateral sclerosis,including the abnormalities in nucleoplasmic transport,RNA function,post-translational modification,liquid-liquid phase separation,stress granules,mitochondrial dysfunction,oxidative stress,axonal transport,protein quality control system,and non-cellular autonomous functions(e.g.,glial cell functions and prion-like propagation).
基金supported by the National Natural Foundation of China(81672007 and 81971920 to Wenran Zhao,81871652 to Zhaohua Zhong,and 81772188 to Yan Wang)Health and Family Planning Commission of Heilongjiang Province(2017-158 to Xiaoman Wo)
文摘Enterovirus A71(EV-A71)is one of the etiological pathogens leading to hand,foot,and mouth disease(HFMD),which can cause severe neurological complications.The neuropathogenesis of EV-A71 infection is not well understood.The mislocalization and aggregation of TAR DNA-binding protein 43(TDP-43)is the pathological hallmark of amyotrophic lateral sclerosis(ALS).However,whether TDP-43 was impacted by EV-A71 infection is unknown.This study demonstrated that TDP-43 was cleaved during EV-A71 infection.The cleavage of TDP-43 requires EV-A71 replication rather than the activated caspases due to viral infection.TDP-43 is cleaved by viral protease 3 C between the residues 331 Q and332 S,while mutated TDP-43(Q331 A)was not cleaved.In addition,mutated 3 C which lacks the protease activity failed to induce TDP-43 cleavage.We also found that TDP-43 was translocated from the nucleus to the cytoplasm,and the mislocalization of TDP-43 was induced by viral protease 2 A rather than 3 C.Taken together,we demonstrated that TDP-43 was cleaved by viral protease and translocated to the cytoplasm during EV-A71 infection,implicating the possible involvement of TDP-43 in the pathogenesis of EV-A71 infection.
