Small junction, big problems: Neuromuscular junction pathology in mouse models of amyotrophic lateral sclerosis (ALS)

Abstract

Amyotrophic lateral sclerosis (ALS) is a motor neuron disease with an extremely heterogeneous clinical and genetic phenotype. In our efforts to find therapies for ALS, the scientific community has developed a plethora of mouse models, each with their own benefits and drawbacks. The peripheral nervous system, specifically the neuromuscular junction (NMJ), is known to be affected in ALS patients and shows marked dysfunction across mouse models. Evidence of pathology at the NMJ includes denervated NMJs, changes in endplate size and loss of terminal Schwann cells. This review compares the temporal disease progression with severity of disease at the NMJ in mouse models with the most commonly mutated genes in ALS patients (SOD1, C9ORF72, TARDBP and FUS). Despite variability, early NMJ dysfunction seems to be a common factor in models with SOD1, TARDBP and FUS mutations, while C9ORF72 models do not appear to follow the same pattern of pathology. Further work into determining the timing of NMJ pathology, particularly in newer ALS mouse models, will confirm its pivotal role in ALS pathogenesis and therefore highlight the NMJ as a potential therapeutic target.

Glutamatergic Synapse Dysfunction in Drosophila Neuromuscular Junctions Can Be Rescued by Proteostasis Modulation

“…Our results thus show changes in the physiology and health of glutamatergic synapses in mutant Q78 Drosophila NMJs. Such changes in NMJs have been previously reported in several neurodegenerative disorders across various models (Menalled et al, 2003;Dupuis and Loeffler, 2009;Steinert et al, 2012;Pratt et al, 2015;Rodríguez Cruz et al, 2020;Alhindi et al, 2021).…”

Antibody-Based Therapeutic Interventions for Amyotrophic Lateral Sclerosis: A Systematic Literature Review

“…In ALS animal models, loss of neuromuscular synapses occurs prior to the loss of motor neurons (Alhindi et al, 2021 ). Although defects in the MuSK signaling pathway are not associated with ALS, studies show that overexpression of MuSK stabilizes neuromuscular synapses in SOD1G93A ALS mouse model, preventing denervation and slowing down motor dysfunction (Pérez-García and Burden, 2012 ).…”

hiPSC-Derived Schwann Cells Influence Myogenic Differentiation in Neuromuscular Cocultures

“…However, species-specific differences complicate translation of disease signs and mechanisms. In comparison to mice, SC at healthy human NMJs exhibit higher non-synaptic placement of their nuclei along with less AChR coverage, which in SOD1 mutant mice would both be associated with pathological changes [ 53 ]. Indeed, mouse model data have so far not been able to translate well into treatments for human ALS [ 54 ].…”