TDP-43 dysregulation and neuromuscular junction disruption in amyotrophic lateral sclerosis

Translational Neurodegeneration

Review

Thomas Martin Durcan¹  Maria José Castellanos-Montiel¹  Sarah Lépine² 

[1] The Neuro’s Early Drug Discovery Unit (EDDU), Department of Neurology and Neurosurgery, Montreal Neurological Institute-Hospital, McGill University, 3801 University Street, H3A 2B4, Montreal, QC, Canada;The Neuro’s Early Drug Discovery Unit (EDDU), Department of Neurology and Neurosurgery, Montreal Neurological Institute-Hospital, McGill University, 3801 University Street, H3A 2B4, Montreal, QC, Canada;Faculty of Medicine and Health Sciences, McGill University, 3605 De La Montagne, H3G 2M1, Montreal, QC, Canada;

关键词: Amyotrophic lateral sclerosis;    Denervation;    Neuromuscular junction;    TDP-43;    Dying-back;    Dying-forward;   

DOI  :  10.1186/s40035-022-00331-z

 received in 2022-09-26, accepted in 2022-11-29,  发布年份 2022

来源: Springer

【 摘 要 】

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 neuromuscular 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.

【 授权许可】

CC BY   
© The Author(s) 2022

【 图 表 】

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