Please use this identifier to cite or link to this item:
Title: The role of MYO9A at the neuromuscular junction
Authors: O'Connor, Emily Ann
Issue Date: 2019
Publisher: Newcastle University
Abstract: Congenital myasthenic syndromes (CMS) are a group of rare, inherited disorders characterised by impaired function of the neuromuscular junction (NMJ). This is due to defects in one of the many proteins associated with the NMJ. Patients with CMS present with fatigable skeletal muscle weakness that can vary in age of onset, severity and muscles affected. In 3 patients with CMS, missense mutations in a gene encoding an unconventional myosin protein, not previously linked to neuromuscular diseases, MYO9A, were identified as likely causing their disorder. Therefore, the aim of this project was to determine whether MYO9A is playing a role at the NMJ and how loss or defective function of this protein may impact signal transmission. This question was addressed using a range of models, including patient fibroblasts converted into neurons, morpholino and CRISPR/Cas9-mediated knockdown zebrafish and a knockout mouse model. Investigation of the NSC-34 cells led to the finding that the cytoskeleton was affected in the absence of MYO9A, and this impacted on the dynamics of intracellular vesicles and endo/exocytosis. Secretome analysis revealed a downregulation of agrin secretion in MYO9A deficient cells, a protein important for the development and function of the NMJ. Analysis of NMJs in MYO9A-depleted zebrafish and mice revealed changes in morphology, including smaller nerve terminals and area of endplates. Due to the suitability of zebrafish for drug screening, fish were treated with a synthetic agrin compound. This rescued a number of the defective features identified in the knockdown fish, thus providing a potential mode of action for this form of CMS and an avenue for patient treatment. This study highlights a role for MYO9A at the NMJ, the first unconventional myosin motor protein associated with a neuromuscular disease, thus opening a new avenue of proteins and pathways that may be relevant for a range of disorders.
Description: Ph. D. Thesis
Appears in Collections:Institute of Genetic Medicine

Files in This Item:
File Description SizeFormat 
O'Connor E 2019.pdfThesis26.65 MBAdobe PDFView/Open
dspacelicence.pdfLicence43.82 kBAdobe PDFView/Open

Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.