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Title: Disease mechanisms in mitochondrial maintenance disorders
Authors: Sitarz, Kamil Sebastian
Issue Date: 2012
Publisher: Newcastle University
Abstract: OPA1 and MFN2 are two critical mitochondrial membrane proteins required for mitochondrial fusion. OPA1 mutations account for approximately 60% of cases of autosomal-dominant optic atrophy (DOA) and up to 20% of mutational carriers develop a more severe multi-systemic neurological phenotype (DOA+) in addition to visual failure. MFN2 mutations result in Charcot-Marie-Tooth disease type 2A (CMT-2A) and in a subgroup of patients, the peripheral neuropathy is complicated by optic atrophy, highlighting a degree of phenotypic overlap with DOA+. POLG1 encodes the catalytic subunit of DNA polymerase gamma (POLG) and POLG1- related diseases are clinically highly heterogeneous, ranging from early-onset Alpers- Huttenlocher syndrome to late-onset isolated chronic progressive external ophthalmoplegia. OPA1, MFN2 and POLG1 mutations all result in disturbed mitochondrial DNA (mtDNA) maintenance, with both quantitative (depletion) and qualitative (point mutations and deletions) mtDNA abnormalities having been identified in patient tissue samples. In this PhD project, the disease mechanisms underpinning these nuclear mitochondrial disorders have been studied further. OPA1 and MFN2 mutations were found to result in significant mtDNA proliferation as a likely compensatory mechanism to impaired mitochondrial oxidative phosphorylation. Using a previously-validated repopulation assay, mtDNA replication in cultured POLG1-mutant fibroblasts was severely depressed following a period of ethidium bromide-induced mtDNA depletion. A similar observation was made with OPA1-mutant fibroblasts, but this effect was not as marked as for POLG1-mutant fibroblasts. Significant reorganisation of the mitochondrial network was also apparent for both groups of mutant fibroblasts. Although neuromyelitis optica (NMO) shares some clinical features with DOA, genetic variations within OPA1 are not associated with the risk of developing NMO. Finally, research into DOA and other mitochondrial optic neuropathies have been severely restricted by the lack of the access to retinal ganglion cells (RGCs), precluding direct studies to be performed on the cell type which is preferentially affected in this group of disorders. To circumvent this limitation, human induced pluripotent stem cell (hiPSC) lines have been generated from patient-derived fibroblasts harbouring confirmed OPA1 mutations. The future differentiation of these induced pluripotent stem cell lines into RGCs will hopefully provide a powerful and versatile tool for disease modelling and the development of targeted therapeutic strategies.
Description: PhD Thesis
Appears in Collections:Institute of Genetic Medicine

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