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.

Keywords: C9orf72; FUS; NMJ; SOD1; TDP-43; denervation; dying-back.

FIGURE 1

Representative confocal images show the marked difference of NMJ morphology between mouse (top panels) and human (lower panels) in peroneus brevis muscles (images taken from data set published in Alhindi et al., 2021). Mouse NMJs are pretzel‐shaped and larger in size, while human NMJs are smaller and have fragmented (nummular‐shaped) endplates. Images have been pseudo‐coloured for display purposes. The panels to the left show a composite image of acetylcholine receptors (magenta) labelled by α‐BTX (alpha‐bungarotoxin), axon and nerve terminals (cyan) labelled by anti‐SV2/2H3, terminal Schwann cells (yellow) labelled by anti‐S100 and nuclei (blue) labelled by DAPI. The panels to the right depict the respective channels in grey scale. Scale bar = 10 µm

FIGURE 2

Timeline of NMJ denervation in the SOD1^G93A mouse model. Blue descriptions indicate ‘clinical’ phenotypes. Green descriptions indicate NMJ changes. Red descriptions indicate motor neuron (MN) loss

FIGURE 3

Timeline of NMJ denervation in C9orf72 mouse models. Blue descriptions indicate ‘clinical’ phenotypes. Green descriptions indicate NMJ changes. Red descriptions indicate motor neuron (MN) loss

FIGURE 4

Timeline of NMJ denervation in TDP‐43 mouse models. Blue descriptions indicate ‘clinical’ phenotypes. Green descriptions indicate NMJ changes. Red descriptions indicate motor neuron (MN) loss

FIGURE 5

Timeline of NMJ denervation in FUS mouse models. Blue descriptions indicate ‘clinical’ phenotypes. Green descriptions indicate NMJ changes. Red descriptions indicate motor neuron (MN) loss