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Title: An investigation into the underlying molecular mechanisms of mitochondrial neurogastrointestinal encephalomyelopathy (MNGIE)
Author: Levene, Michelle
ISNI:       0000 0004 6060 384X
Awarding Body: St George's, University of London
Current Institution: St George's, University of London
Date of Award: 2016
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Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare and fatal inherited metabolic disorder due to a mutation in the nuclear TYMP gene leading to a deficiency in the enzyme thymidine phosphorylase. This subsequently causes an accumulation of the deoxynucleosides, thymidine, and deoxyuridine in tissues and body and ultimately leads to mitochondrial failure. The understanding of the precise molecular mechanisms of this effect and how it influences disease phenotype has been largely hampered by the lack of a disease specific model that accurately reflects MNGIE disease. This thesis aims to address this by exploring the use of human skeletal muscle satellite cells (HSkMSCs) cultured in conditions mimicking the metabolic perturbations found in MNGIE and the molecular profiling of patient serum, serum-derived exosomes, and HSkMSCs. MicroRNA profiling by qPCR panel arrays generated a large number of up-and down-regulated miRNAs. Analysis of these datasets revealed a complex picture of target genes. The upregulation of two creatine kinase (CK) genes was identified with the serum and HSkMSCs, being consistent with the clinical observation of elevated levels of CK in patient plasma, and supports the findings of HSkMSCs releasing increased levels of CK into cell supernatants. The upregulation of genes encoding the five mitochondrial respiratory chain complexes was identified, suggesting compensatory mechanisms within the mitochondrial OXPHOS system in response to A TP deficiency from dysfunctional mitochondria. Signalling pathway genes for MAPKIERK proteins were upregulated, which has been associated with impairment of neural cell migration, neurogenesis, and synapse formation. Molecular profiling has enabled genes to be identified which could potentially have a role in the pathogenesis of MNGIE.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available