Fig. 1

Potential mechanisms underlying MN dysfunction and NMJ disruption via dysregulated TDP-43. In the healthy cell, TDP-43 is involved in several key cellular functions including transcription, splicing, microRNA biogenesis, DNA repair, axonal transport, and translation. In the context of ALS, TDP-43 nuclear depletion, cytoplasmic mislocalization and aggregation may critically alter its functions, eventually leading to NMJ dismantling and MN loss. a Dysregulated TDP-43 may lead to synaptic destabilization through mis-splicing and/or altered expression of transcripts encoding proteins with critical roles at the NMJ. b Defective anterograde axonal transport of mRNAs along with impaired transport-translation coupling may impact local protein synthesis at presynaptic membranes, thereby compromising the integrity of NMJs. Impairments in retrograde axonal transport may disrupt the long-range signal transduction required to respond appropriately to external stimuli and maintain NMJ integrity and function. c Pathologically altered TDP-43 may confer increased susceptibility to activation of the Wallerian degeneration pathway, leading to axonal fragmentation and retraction of motor terminals. d Oxidative stress, enhanced mitochondrial localization of TDP-43 along with abnormal mitochondrial morphology and distribution may induce the loss of MNs and NMJs. e Failure of DNA repair mechanisms mediated by TDP-43 may trigger distal axonal defects and NMJ dismantling. f TDP-43 condensates may sequester mRNAs, microRNAs and proteins, thereby depleting MNs of key factors for NMJ maintenance