A murine model of aging-related neurodegeneration caused by a defect in DNA repair
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ERCC1 is a DNA repair protein that forms a heterodimer with XPF. The resultant dimer is active in multiple systems of DNA repair. Mutations in this repair mechanism result in progeroid syndromes, such as Xeroderma Pigmentosum. These syndromes present with progressive neurodegeneration and are modeled by deletion or transgenic knock down of the ERCC1 gene in mice. Global knockouts and Ercc1-/Δ mice, in which only 5% of the normal compliment of ERCC1 is expressed, have been studied in order to elucidate the cause of the neural pathology. These models, similar to patients, often show neurodegeneration, but it was unclear whether this loss was due to a primary neuronal dysfunction or that of supporting glial cells. L7Cre;Ercc1-/cond mice, in which Ercc1-XPF is deleted only in the neurons of the forebrain, are used in this study to determine the cell autonomous impact of DNA repair deficiency on neurons. Oxidative damage is thought to contribute to the progression of aging- related neurodenerative disease, such as AD and PD, and DNA could be a prominent target. The hypothesis that pathology in L7Ercc1-/cond mice is similar to that of neurodegenerative disease states was supported in many instances. The decrease in weight seen in mutant mice is also seen in patients with both AD and PD. The degeneration in the hippocampus and alteration in DG proliferation is consistent with that often seen in AD, as is cortical degeneration and thinning of the corpus callosum. Gliosis in the striatum is seen in many PD patients and could be contributing to the ambulation impairment seen in the mutant mice. These data suggest a link between DNA repair deficiency and neurodegeneration stemming from multiple origins. Elucidating the impact of unrepaired endogenous DNA damage on neurons using this genetic tool may allow for the development of future interventions to slow aging-related neurodegeneration, as well as the progression of AD and PD.
Thesis (M.A.)--Boston University