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

Abstract

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.

Scalable, optically-responsive human neuromuscular junction model reveals convergent mechanisms of synaptic dysfunction in familial ALS

“…These results suggest both a morphological and functional defect in ALS NMJs. Our histological assessment and MEA electrophysiological recordings of NMJs derived from ALS patient iPSCs and respective controls recapitulate NMJ phenotypes that have been reported in the literature 3,40,53,54 . Because of the consistency and scalability of our method, as well as its proven sensitivity to detect relevant disease phenotypes within a week of motor neuron and skeletal muscle co-culture, our platform provides a new, promising avenue for high-throughput screening and potential therapeutic discoveries for ALS and other NMDs.…”

Homozygous ALS-linked mutations in TARDBP/TDP-43 lead to hypoactivity and synaptic abnormalities in human iPSC-derived motor neurons

“…Accumulating evidence suggests that TDP-43 is involved in synaptic functions, both at central and neuromuscular synapses (reviewed in (Gulino, 2023;Lépine et al, 2022;Ling, 2018)).…”

“…Accumulating evidence suggests that TDP-43 is involved in synaptic functions, both at central and neuromuscular synapses (reviewed in (Gulino, 2023; Lépine et al, 2022; Ling, 2018)). Pathologically altered TDP-43 has been shown to perturb the expression of synaptic genes in ALS mouse models and patients (Brown et al, 2022; Ma et al, 2022; Mishra et al, 2007; Polymenidou et al, 2011).…”

“…Accumulating evidence suggests that TDP-43 is involved in synaptic functions, both at central and neuromuscular synapses (reviewed here [86][87][88] ). Pathologically altered TDP-43 has been shown to perturb the expression of synaptic genes in ALS mouse models and patients.…”

Application of spatial transcriptome technologies to neurological diseases

“…Motor neuron degeneration in amyotrophic lateral sclerosis (ALS) results in muscle denervation atrophy (Lepine et al, 2022). Therefore, it is crucial to use spatial transcriptomics to collect and examine changes in ALS gene expression in order to identify cellular subpopulations associated with each stage of the disease process and to investigate the underlying molecular mechanisms that cause and sustain the disease.…”