Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.677032
Title: On the role of prelamin A in the heart
Author: Brayson, Daniel James
ISNI:       0000 0004 5368 1970
Awarding Body: King's College London
Current Institution: King's College London (University of London)
Date of Award: 2014
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Abstract:
Prelamin A is one of two protein products of the LMNA gene and undergoes proteolytic processing to become mature lamin A, a crucial protein for nuclear envelope structure and function. Evidence suggests that when this process is hindered, resulting in accumulation of prelamin A, premature ageing disorders and cardiovascular complications occur. Moreover, mutations to LMNA are known to lead to dilated cardiomyopathy (DCM), with some of these mutations possibly resulting in accumulation of prelamin A, thus potentially implicating prelamin A in DCM pathogenesis. To explore whether prelamin A has a role in DCM and heart disease, I used targeted transgenesis to the Rosa26 locus of the mouse genome of an uncleavable prelamin A construct (L647R-LMNA). Cardiac selective expression was achieved via MLC2v promoter linked cre-recombinase mediated cassette exchange to yield mice which expressed prelamin A exclusively in cardiomyocytes—PLA Tg mice. They were compared to mice harbouring but not expressing the transgene, referred to as Wildtype (Wt). Compared to Wt, PLA Tg mice failed to thrive and succumbed at 5-6 weeks of age from a phenotype indicative of DCM and heart failure as defined by echocardiographic analysis of cardiac function, i.e. ejection fractions were dramatically reduced in PLA Tg (19.56%) compared to Wt (60.6%). Additional characterisation identified myocardial disarray and inflammation, and cardiomyocyte death as occurring in PLA Tg heart tissue. Molecular characterisation suggested accumulation of DNA damage leading to ATM mediated NF-κB signalling may initiate inflammation of the myocardium and may also contribute to ‘myocardial senescence’. Disruption of gap junction formation via Cx43 mislocalisation occurred and later structural proteins of the nuclear envelope were misexpressed and disorganised, indicating that cardiomyocytes were susceptible to mechanical stress in the face of prelamin A accumulation. Immunofluorescence staining of human heart showed that prelamin A accumulated in the nuclei of a number of DCM heart biopsies, strongly implicating a role for prelamin A accumulation in clinical DCM pathogenesis. Moreover, it was observed that prelamin A was expressed, in low levels, endogenously in Wt myocardium and may be a novel component of the sarcomere. In conclusion, this thesis provides evidence that nuclear prelamin A accumulation occurs in certain settings of DCM pathogenesis which may be a direct consequence of LMNA mutations or which may occur downstream of other pathogenic events. In this setting, prelamin A may mediate pathology via mechanisms identified in PLA Tg mice.
Supervisor: Shanahan, Catherine Mary ; Shah, Ajay Manmohan Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.677032  DOI: Not available
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