Abstract

Dementia with Lewy bodies (DLB) is the second most common form of dementia. The condition is neuropathologically characterised by widespread Lewy body deposition within neurons, and frequently by impairment of complex I activity of the mitochondrial respiratory chain. High levels of mitochondrial DNA (mtDNA) mutations have been observed in post mortem cases, though their contribution to the pathology is not understood. Using ultra-high depth next generation sequencing technology in human post -mortem tissue on a homogenate and single cell level, I am to determine: (1) whether mitochondrial DNA mutations correlate with regional pathology, (2) whether mtDNA mutations cause complex I deficiency and (3) whether observed mtDNA mutations are likely to have been acquired or inherited. In parallel, crossing of transgenic mice containing a mutation in mtDNA polymerase (POLG) causing mtDNA mutations, and mice harbouring a pathogenic alpha-synuclein mutation, I will determine whether mtDNA muta tions potentiate Lewy body pathology in vivo, and thus contribute to pathogenesis. Understanding the role of mtDNA mutations in DLB and the relative contribution of inherited and acquired variants could drastically alter our understanding of the disease and our approach to clinical testing and the development neuroprotective therapies.