Universität zu Köln

Albarran Gutierrez, Sara Ruth (2020). Molecular mechanisms underlying the rate of progeria onset in mtDNA mutator mouse strains. PhD thesis, Universität zu Köln.

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Abstract

The mtDNA mutator mouse model contains a D257A mutation in the exonuclease domain of the POLG gene, which generates a mouse with an increased number of mtDNA mutations. The mouse shows several characteristics of premature ageing. To date, three mutators with the same POLG mutation have been described in the literature. However, they show remarkable differences in lifespan and the time when the ageing phenotype appears. This study has demonstrated that although the genetic background influences to some degree the ageing phenotype, the main cause of the phenotypical differences exhibited by two of the mutator mice strains is due to the POLG allele expressed (Lar allele versus the Pro allele) and not the nuclear genetic background. In addition, my work has revealed that the Pro allele generates a variant protein product of POLG, and as a result, the mutator mouse with this variant shows a slightly different phenotype than the mutator with the Lar allele. Pro mutator mouse phenotype differences include male fertility, increased lifespan, slower onset of the ageing phenotypes, reduced mutation rate, reduced mitochondrial dysfunction and different replicative activity.