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Title: The role of eEF1A2 in the pathogenesis of motor neurone disease in wasted mice
Author: Dharmasaroja, Permphan
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2007
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Mice with autosomal recessive gene wasted (wsf) develop a set of neurological features that include progressive muscle wasting, weight loss, progressive paralysis, and degeneration of motor neurones in spinal cord and brainstem. The wasted mutation is caused by a 15.8-kilobase deletion that completely abolishes the detectable expression of eukaryotic elongation factor 1A2 (eEF1A2), a tissue specific protein that expresses only in nervous system, heart and skeletal muscle. In this PhD thesis I describe the characterisation of neuromuscular abnormalities of wasted mice and study expression of nerve-regulated genes using real-time RT-PCR.  Muscle of wasted mice showed evidence of denervation atrophy, and the patterns of gene expression were characteristic for the type of denervation. I have constructed an epitope-tagged eEF1A2 plasmid and studied colocalisation of eEF1A2 and spinal motor neurone (SMN) protein in HeLa cells, using quantitative immunocolocalisation analysis. I have shown that a proportion of cytoplasmic eEF1A2 colocalises with SMN. To study the role of eEF1A2 I have constructed a muscle-specific transgene and generated transgenic homozygous wasted mice that specifically express human eEF1A2 in skeletal muscle, but not in neurones. Transgenic wasted mice showed the same phenotype as spontaneous mutant wasted mice. Muscle pathology and the patterns of gene expression were compatible with denervation. These findings suggest that the loss of eEF1A2 in motor neurone, but not muscle, leads to muscle atrophy in wasted mice.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available