TDP-43 dysregulation and neuromuscular junction disruption in amyotrophic lateral sclerosis.
Sarah LépineMaria José Castellanos-MontielThomas Martin DurcanPublished in: Translational neurodegeneration (2022)
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.
Keyphrases
- amyotrophic lateral sclerosis
- end stage renal disease
- palliative care
- induced apoptosis
- chronic kidney disease
- newly diagnosed
- ejection fraction
- multiple sclerosis
- machine learning
- cell cycle arrest
- cell death
- early onset
- oxidative stress
- peritoneal dialysis
- patient reported outcomes
- single molecule
- signaling pathway
- dna methylation
- late onset
- room temperature
- patient reported