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

• Published in: Journal of anatomy Vol. 241; no. 5; pp. 1089 - 1107
• Main Authors: Alhindi, Abrar, Boehm, Ines, Chaytow, Helena
• Format: Journal Article
• Language: English
• Published: Oxford Wiley Subscription Services, Inc 01.11.2022; John Wiley and Sons Inc
• Subjects: Amyotrophic lateral sclerosis; Animal models; C9orf72; denervation; dying‐back; FUS; FUS gene; Motor neuron diseases; Nervous system; Neuromuscular junctions; NMJ; Pathology; Patients; Phenotypes; Review; Rodents; Schwann cells; SOD1; Superoxide dismutase; TDP‐43; Therapeutic targets
• ISSN: 0021-8782; 1469-7580
• DOI: 10.1111/joa.13463

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. Summary of neuromuscular junction (NMJ) changes across ALS mouse models. ALS mouse models show different levels of NMJ pathology depending on gene targets: SOD1, TDP‐43 and FUS models all show initial NMJ dysfunction prior to motor neuron death (arrows), supporting a ‘dying‐back’ theory, while C9orf72 NMJ pathology is less clear. Terminal Schwann cells (tSCs) are lost in the SOD1 model. Dark red regions on the muscle fibre represent the endplate, which is smaller and fragmented in some C9orf72, TDP‐43 and FUS models.