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Title: The effects of ASD-linked eIF4E dysregulation on protein synthesis in an in vitro system of neuronal differentiation
Author: Anderson, Jihan
Awarding Body: University of Aberdeen
Current Institution: University of Aberdeen
Date of Award: 2018
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Autism is a lifelong, neurodevelopment disorder characterised by repetitive patterns of behaviour and impairments in social interaction. Previously identified mutations in Autism Spectrum Disorder individuals suggests aberrant translation initiation in the pathogenesis of the disorder. The eukaryotic translation initiation factor eIF4E is one such example and the focus of my research has been to elucidate its role in Autism Spectrum Disorders. eIF4E has a key role in translation-dependent synaptic plasticity; a process critical in learning and memory. Studies which altered eIF4E expression in mice witnessed an autistic-like phenotype which could be reversed upon pharmacological control of eIF4E activity; further implicating aberrant protein synthesis in autism spectrum disorders. To analyse the effects of dysregulated eIF4E in neural stem cells differentiated into neurons, I introduced additional copies of EIF4E into these cells. By comparing proteomes of control and eIF4E expressing neurons, I identified changes in a few select proteins including various neurofilaments, intermediate filaments, and MAP2. Neurofilaments are core proteins in the neuronal cytoskeleton and determine axon calibre which define neural signal transduction rates. Furthermore, the vesicular GABA, and glutamate transporter, neuroligin-2 and synaptotagmin-1 also exhibited changes in their expression with dysregulated eIF4E. These proteins are involved in maintaining neural homeostasis and as such, a shift in their expression can alter the excitatory/inhibitory balance; a phenomenon linked to autism spectrum disorders. In summary, these findings further illustrate the importance of eIF4E in translation initiation in neurons, and highlight its role in the regulation of proteins with key roles at the synapse to help maintain neural homeostasis.
Supervisor: Müller, Berndt ; Donaldson, Anne D. ; McCaig, Colin D. ; Rao, Francesco Sponsor: Medical Research Scotland
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Autism spectrum disorders ; Neuroplasticity ; Proteomics ; Proteins