Analysis of the role of the Parkinson's disease-linked protein DJ-1 in mitophagy

Parkinson’s disease is a very common brain disease characterized by slowness of movement, tremor, falls, dementia and many other problems. There is still no therapy that slows down its relentless progression. In Parkinson’s disease dopamine-producing nerve cells in the brain gradually die. Why these cells die, is not well understood. In some familial cases Parkinson’s disease is caused by genetic mutations. Rare mutations in the genes for parkin, PINK1 and DJ-1 all cause a particular subtype of Parkinson’s disease with specific clinical and genetic characteristics. Parkin and PINK1 are crucial for the maintenance of a healthy pool of mitochondria in the cell. Mitochondria are organelles that produce energy but, when damaged, can induce cell death. Sick mitochondria must therefore be eliminated if the cell is to survive. When mitochondria become damaged, Parkin and PINK1 cooperate to label them for selective destruction, a process called mitophagy. Parkinson mutations in the genes for parkin and PINK1 disrupt mitophagy. Very recently, we have found that DJ-1 is also required for mitophagy. In this project, we will unravel the mechanisms by which DJ-1 mediates mitophagy. We will investigate this in skin cells from Parkinson’s disease patients with DJ-1 and parkin mutations and from healthy controls, in neurons derived from these skin cells and in fruit fly models. This work may identify new molecular targets for future therapies to slow down the course of the disease.