Identification and characterisation of novel marker proteins involved in X-linked muscular dystrophy
Lewis, Caroline (2010) Identification and characterisation of novel marker proteins involved in X-linked muscular dystrophy. PhD thesis, National University of Ireland Maynooth.
Progressive X-linked muscular dystrophy represents the most commonly inherited neuromuscular disorder in humans. Although the primary abnormality lies with the loss of dystrophin and reduction of its associated glycoprotein complex, secondary alterations in metabolic pathways, cellular signalling and ion homeostasis regulation cause fibre degeneration leading to severe muscle weakness. Skeletal muscle deteriorates to the extent that sufferers are wheelchair bound by early adulthood and severe diaphragm degeneration can lead to respiratory failure. Therapy in this area has lengthened life-span but at a more advanced stage of the disease, most Duchenne muscular dystrophy patients suffer cardiomyopathic complications. The purpose of this study was to carry out proteomic profiling on differentially affected dystrophic tissues. Differences in protein concentration levels of the severely affected cardiac muscle and the naturally protected extraocular muscle were used to explore pathogenesis of the disease. A mass spectrometry-based approach combined with the highly sensitive difference in-gel electrophoresis technique was used to reveal changes and identify novel biomarkers in the dystrophic tissues. Following the pathogenesis of the disease the naturally protected tissue displayed only moderate changes in protein concentration expression. With a replacement of dystrophin with its homologue utrophin, restoration of β-dystroglycan was observed along with an increased concentration in heat shock proteins. While the severely affected cardiac muscle exhibited drastic decreases in the expression levels of many proteins involved in energy metabolism including adenylate kinase and many ATP synthase isoforms. Reduced concentrations were also observed in numerous contractile proteins and intermediate filament proteins. With the loss of these structural elements, a drastic increase in stress proteins was observed within dystrophic myofibrils compared to normal fibres. This thesis has successfully identified novel biomarkers that may be used to determine suitability of new treatments or therapies of muscular dystrophy.
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