Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.595092
Title: The regulation of dystroglycan function in skeletal muscle
Author: Lipscomb, Leanne
Awarding Body: University of Sheffield
Current Institution: University of Sheffield
Date of Award: 2013
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Abstract:
Dystroglycan is central to the dystrophin-associated glycoprotein complex (DGC), which helps provide stability to muscle fibres. The absence of dystrophin in Duchenne muscular dystrophy results in the loss of this complex. The phosphorylation of β-dystroglycan is thought to play an important role in controlling the integrity of the DGC. This phosphorylation event has been shown to promote β-dystroglycan internalisation, possibly as a prerequisite to degradation. The work presented in this thesis aimed to use the zebrafish to investigate new therapeutic approaches to restore dystroglycan to the membrane and assess the extent to which muscle attachments can be strengthened in the dystrophin mutant zebrafish (sapje). As in mammals, the stability of the zebrafish DGC is dependent on dystrophin expression. As such, β-dystroglycan levels in sapje decreased in an age-dependent manner. Loss of dystrophin led to an initial elevation in phosphorylated β-dystroglycan levels. Treatment of sapje fish with proteasome and kinase inhibitors was able to prevent or slow the progression of dystrophy, in a dose-dependent manner. This was associated with a concomitant increase in dystroglycan and decrease in phosphorylated dystroglycan. This work provides insight into the molecular mechanisms that lead to the loss of dystroglycan from the membrane in dystrophic muscles, and may have therapeutic implications in the future.
Supervisor: Winder, Steve Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.595092  DOI: Not available
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