Role of somatic mitochondrial DNA mutations in vulnerability to α-synuclein toxicity
Harvard Medical School, Beth Israel Deaconess Medical Center
Supervising Advisor: Dr. David Simon
The incidence of Parkinson’s disease (PD) rises dramatically with age, but the mechanisms linking aging and PD are unclear. We and others have shown that we accumulate new (acquired) mitochondrial DNA (mtDNA) mutations in neurons as we age, and that these mutations reach particularly high levels in vulnerable dopamine-producing neurons in PD. Acquired mtDNA mutations also have been shown to cause impaired mitochondrial function. We hypothesize a link between these somatic mtDNA mutations and vulnerability to a protein called alpha-synuclein (αSyn). αSyn is a protein that accumulates in vulnerable brain cells in PD and contributes to neurodegeneration. We hypothesize that the age-related accumulation of acquired mtDNA mutations enhances vulnerability to αSyn toxicity. We will specifically test this hypothesis using an error-prone mutant form of the enzyme that replicates mtDNA (POLG). These mice accumulate high levels of acquired mtDNA mutations, leading to features of premature aging and early death at about 15 months of age. We will test our hypothesis by increasing levels of expression of αSyn in different ways in the brains of the POLG mice. These studies will test our hypothesis that acquired mtDNA mutations contribute to vulnerability to αSyn toxicity. If proven to be correct, then these data also would highlight the need to test if strategies to reduce levels of aquired mtDNA mutations, which we and others already have identified, will protect against ɑSyn toxicity. These studies also will characterize a potentially unique and valuable mouse model of PD that incorporates 2 distinct pathophysiologically relevant mechanisms.