Marrosu, Elena;
(2022)
Characterisation of a novel interaction of dystrophin with caveolae in the heart.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
Patients living with Duchenne and Becker muscular dystrophy are characterised respectively by the loss of a functional dystrophin protein and the expression of a mutant dystrophin protein. Dilated cardiomyopathy (DCM) is the major cause of death in these patients and the molecular mechanisms causing DCM in these patients are still not completely established. In fact, the cardiac disease is treated with cardioprotective drugs that delay but do not prevent DCM as a targeted treatment for the heart is still not available due to this lack of knowledge. Previous findings showed that exclusively in the heart, the dystrophin glycoprotein complex includes cavin-1, an essential protein for the biogenesis of caveolae. Caveolae in the heart are involved in mechanisms of cardio protection, cardiac contraction, and cardiac conduction. Key caveolae accessory proteins include cavin-2, -3 and -4. More importantly, caveolar protein mutations have been linked to cardiomyopathy. My PhD thesis investigates the molecular interactions between cardiac dystrophin and cavins that are important for cardiac function and are affected by dystrophin gene mutations. I have characterised the distribution of cavin proteins in mouse, rat and dog models of Duchenne muscular dystrophy (DMD) comparing this distribution in explanted human heart and discovered that cavin-1 and -4 cardiac localisation is conserved across these different species. I have investigated the effect of the loss of full-length dystrophin in DMD mouse, rat and dog models finding different levels of disruption of cavin-1 and -4 that could be attributed by the expression of shorter dystrophin isoforms in these animal models. I have also tested the ability of five different micro and mini-dystrophin (one of them is currently used in a clinical trial) constructs in restoring the physiological cardiac localisation of cavin-1 and -4 finding that none of them is able to do this. Overall, my findings suggest that the cardiac localisation of cavins is dependent on the expression of dystrophin at the cardiomyocyte membrane and that the cavin binding domain could reside in the distal part of the dystrophin protein. This knowledge suggests new roles of dystrophin in the heart and could be useful for the design of the next gene therapy constructs and for the development of targeted cardiac therapies.
Type: | Thesis (Doctoral) |
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Qualification: | Ph.D |
Title: | Characterisation of a novel interaction of dystrophin with caveolae in the heart |
Open access status: | An open access version is available from UCL Discovery |
Language: | English |
Additional information: | Copyright © The Author 2022. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. |
UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Developmental Neurosciences Dept UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences |
URI: | https://discovery.ucl.ac.uk/id/eprint/10155460 |
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