Meyer, Ione Frederica Greensmith; (2019) Investigating the role of nidogens, a family of basement membrane proteins, at the neuromuscular junction in health and disease. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The basement membrane is a specialised form of the extracellular matrix that surrounds cells and tissues to provide structural support, regulate tissue development and modulate homeostatic signalling. Despite the ubiquitous presence of this matrix throughout the body, dysregulation of individual components can result in tissue-specific human diseases. Recently nidogens, a family of basement membrane glycoproteins, have been identified as candidate genes in a family with hydrocephalus and muscle weakness. Increasing evidence suggests that nidogens are involved in signalling processes underlying neurological function and development, and certain nidogen isoforms appear to be specific to the neuromuscular junction (NMJ). My aim was to investigate the active signalling role of nidogens at the NMJ using a combination of biochemical and imaging techniques. As the basement membrane can play an important role in tissue remodelling, I investigated the changes in expression profile of nidogens in conditions of NMJ plasticity. Expression was measured during postnatal muscle maturation and disease progression in a model of amyotrophic lateral sclerosis (ALS) - the SOD1G93A mouse. As neurotrophins are crucial to the development and maintenance of motor neurons and NMJs, I also investigated the interaction of nidogens with several trophic molecules. My work shows that nidogens are internalised by motor neurons and may be co-transported with neurotrophin receptors inside signalling endosomes. While expression of nidogens appears unaffected by disease progression in the SOD1G93A mouse, there may be increased levels of nidogens and altered isoform expression during early postnatal muscle maturation. I also introduce a novel nidogen-1 knock-out mouse model, which displays neurological phenotypes and compensatory upregulation of nidogen-2 in certain tissues. Defining the nidogen signalling complex and its downstream pathways will increase our understanding of the homeostatic mechanisms governing the NMJ and provide new targets for therapeutic strategies to maintain neuromuscular function in pathological conditions.

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