Mejia Maza, Alan Jesus; (2020) Dissecting pathology in mouse models in Amyotrophic Lateral Sclerosis and Charcot-Marie-Tooth disease. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Neuromuscular junctions (NMJs) are the synapses connecting motor neurons to muscle fibres. Dysfunction of the NMJ has been implicated in the pathology of amyotrophic lateral sclerosis (ALS) and Charcot-Marie- Tooth (CMT) disease, partly due to the progressive loss of skeletal muscle control in these disorders, and due to the common final NMJ phenotype, regardless of the genetic mutation. These motor system diseases are associated with skeletal muscle fibre and protein pathologies in the central or peripheral nervous system. Modelling NMJ dysfunction using mouse models is important for us to investigate pathological mechanisms and to identify how gene mutations involved in diverse biological functions lead to a common NMJ phenotype. However, NMJ structural studies are based mostly on manual analysis with potential intra- and inter-rater variability, limiting reproducibility. Methods: Mouse models of ALS and CMT were investigated, each containing a single mutation caused by transgenic or knock-in technology or chemical mutagenesis. We carried out an extensive pathological analysis in the nervous tissues and hindlimb muscles in the ALS mice and NMJ studies in both ALS and CMT mice. The NMJ studies were further developed by creating a python- script coupled to a machine learning algorithm. Results and discussion: To address the subjective nature of manual NMJ analysis, we developed a novel high-throughput screening method for NMJ structural analysis and a machine learning system for automatic identification of NMJ innervation status. Using this system, ‘NMJ analyser’ we have identified changes in multiple morphological parameters across ALS and CMT mouse strains supporting the idea that the NMJ denervation process seems to be different in these models. Furthermore, within FUS-ALS mice, we did not find upper motor neuron loss and gliosis in the motor cortex nor fibretype pathology at multiple timepoints analysed. Our results lead to a 1) more comprehensive and precise study of NMJ pathology, 2) systematic study of NMJs in mice and 3) precise identification of NMJ morphological changes across different mouse models with NMJ pathology. Further understanding of NMJ denervation process could lead to novel and earlier therapeutic interventions in patients where NMJ pathology is observed.

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