Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.543480
Title: The effect of farnesylated prelamin A accumulation on nuclear morphology and function
Author: Goulbourne, Christopher Nicholas
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2011
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Abstract:
Failure to process prelamin A, by the enzyme ZMPSTE24, leads to the build up of farnesylated prelamin A, which has been implicated in causing the symptoms experienced in laminopathies and HIV therapy. A common feature to these conditions is the development of an irregular nuclear boundary, often including deep invaginations that form a nucleoplasmic reticulum. Additionally, dysregulated lipid synthesis is frequently associated with improper lamin A processing and I set out to address the molecular mechanisms behind these two features that could explain lipoatrophy experienced in patients. By using siRNA targeted against Zmpste24 I utilised an array of biochemical, molecular and imaging techniques to uncover a mechanism that leads to the production of a nucleoplasmic reticulum that was dependent on both the farnesylated tail of prelamin A and the phosphatidylcholine synthesising enzyme CCTα. The morphology of this structure consisted of an invagination of both the inner and outer nuclear membranes with a cytoplasmic core or just invagination of the inner nuclear membrane. Serial section dual axis electron tomography provided a new insight into the ultrastructural changes at the nuclear periphery that revealed novel structural features. The dysregulation of lipid synthesis was assessed by investigating the effects farnesylated prelamin A has on the distribution and dynamics of the transcription factor SREBP-1 and assessment of the downstream consequences this has on its targets that regulate adipocyte differentiation potential. Finally, the metabolomic profile of an HIV protease inhibitor that leads to prelamin A build up was generated and revealed increases in lipolysis, glycolysis and mediators of inflammation. The research presented offers a new insight into the development of a convoluted nuclear boundary and nucleoplasmic reticulum, in the context of lamin A mutants and how dysregulated lipid synthesis, caused by farnesylated prelamin A, leads to lipoatrophy.
Supervisor: Vaux, David Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.543480  DOI: Not available
Keywords: Biology ; Cell Biology (see also Plant sciences) ; Metabolism ; Biology (medical sciences) ; Disease prevention ; Pathology ; Mass spectrometry ; Membrane proteins ; nuclear morphology ; lamin ; laminopathies ; prelamin A ; lipoatrophy ; HIV protease inhibitor ; nucleoplasmic retciulum ; metabolomics
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