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Title: Characterisation of a zebrafish model of Wolfram Syndrome
Authors: Cairns, George Edward
Issue Date: 2019
Publisher: Newcastle University
Abstract: Wolfram Syndrome (WS), is a neurodegenerative disorder defined historically by the combination of diabetes insipidus, diabetes mellitus, optic atrophy and sensorineural deafness (DIDMOAD). The majority of patients with WS harbour recessive mutations within the WFS1 gene (OMIM 606201), which encodes the wolframin protein. Wolframin is implicated in a number of critical cellular pathways, in particular the ER stress response and calcium homeostasis. Mitochondrial dysfunction is suspected to play a key role in the pathology of the disease. This link is highlighted by mutations in the CISD2 (OMIM 611507) gene, which also result in WS through a deleterious effect on mitochondrial calcium flux and disturbed ER-mitochondrial interactions. Wolframin is also suspected to have a role in the development of the brain and neuronal tissue and is associated with numerous neurological and psychiatric disorders. The aim of this study was to characterise novel zebrafish models (wfs1a & wfs1b) of WS to further our understanding of the role of wolframin in WS, particularly in regulating mitochondrial function and neuronal development. This model could also be used to screen for therapeutic compounds. The characterisation of this zebrafish model involved observing histological, behavioural and biochemical changes in the knockout zebrafish and determining if the model was comparable to the pathological features reported in patients with WS. We have shown that this zebrafish model of WS shares defects in the ability to cope with ER stress and importantly, it shares similar phenotypes to the human, in particular optic atrophy. Mitochondrial dysfunction was also observed in the model with changes seen in trafficking, respiration and changes in expression of Complex I of the mitochondrial electron transport chain. This zebrafish model provides a powerful tool to observe neuronal development and mitochondrial function in a live animal model, providing new insights on the mechanisms driving neuronal degeneration in WS.
Description: PhD Thesis
Appears in Collections:Institute of Genetic Medicine

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