Cryptic single-cell mitochondrial DNA mutations in human brain aging and neurodegeneration

The prevalence of neurodegenerative disorders is increasing at an alarming rate, but our limited understanding of disease mechanisms has impeded the development of new treatments. The association between mitochondrial DNA (mtDNA) mutations, ageing and disease has been known for some time, but a causal link is mostly supported by extreme mouse-mutants or rare human genetic diseases. Our preliminary analysis has uncovered an unexpected, and enormous, diversity of hidden (or ‘cryptic’) mtDNA mutations at the single-cell level in aged humans. We have established new mathematical and experimental methods enabling us to show the functional consequences of these cryptic mutations, and have preliminary evidence they have aging-like effects on gene-expression which can be controlled by caloric-restriction. Here we will map the accumulation of cryptic-mtDNA-mutations in the human brain throughout the life-course, and then model this process in mice. We will determine whether three interventions can decelerate cryptic-mutation accumulation, and thereby slow progression in mouse models of Parkinson’s disease. Parkinson’s disease has been closely linked to age-related mtDNA mutations in humans. We anticipate this will show a direct link between the accumulation of cryptic-mtDNA-mutations in single-cells and age-related pathology at the single-cell level, and show that this is amenable to therapeutic manipulation.