Amyotrophic lateral sclerosis(ALS)is a disease characterized by upper and lower motor neuron(MN)loss with a signature feature of cytoplasmic aggregates containing TDP-43,which are detected in nearly all patients.Mutat...Amyotrophic lateral sclerosis(ALS)is a disease characterized by upper and lower motor neuron(MN)loss with a signature feature of cytoplasmic aggregates containing TDP-43,which are detected in nearly all patients.Mutations in the gene that encodes TDP-43(TARBDP)are known to result in both familial and sporadic ALS.In ALS,disruption of neuro-muscular junctions(NMJs)constitutes a critical event in disease pathogenesis,leading to denervation atrophy,motor impairments and disability.Morphological defects and impaired synaptic transmission at NMJs have been reported in several TDP-43 animal models and in vitro,linking TDP-43 dysregulation to the loss of NMJ integrity in ALS.Through the lens of the dying-back and dying-forward hypotheses of ALS,this review discusses the roles of TDP-43 related to synaptic function,with a focus on the potential molecular mechanisms occurring within MNs,skeletal muscles and glial cells that may contribute to NMJ disruption in ALS.展开更多
基金the Faculty of Medicine and Health Sciences of McGill University(to SL),a Canadian Mitacs Accelerate fellowship and ALS Canada trainee award(to MJCM).TMD acknowledges support from the Canada First Research Excellence Fund,awarded through the Healthy Brains,Healthy Lives initiative at McGill University,the CQDM FACs program,a US Department of Defense-ALS Discovery research grant and a project grant from CIHR(PJT-169095).
文摘Amyotrophic lateral sclerosis(ALS)is a disease characterized by upper and lower motor neuron(MN)loss with a signature feature of cytoplasmic aggregates containing TDP-43,which are detected in nearly all patients.Mutations in the gene that encodes TDP-43(TARBDP)are known to result in both familial and sporadic ALS.In ALS,disruption of neuro-muscular junctions(NMJs)constitutes a critical event in disease pathogenesis,leading to denervation atrophy,motor impairments and disability.Morphological defects and impaired synaptic transmission at NMJs have been reported in several TDP-43 animal models and in vitro,linking TDP-43 dysregulation to the loss of NMJ integrity in ALS.Through the lens of the dying-back and dying-forward hypotheses of ALS,this review discusses the roles of TDP-43 related to synaptic function,with a focus on the potential molecular mechanisms occurring within MNs,skeletal muscles and glial cells that may contribute to NMJ disruption in ALS.
