Grant: Project Grant

Hereditary mutations in PINK1 cause a familial form of Parkinson's disease (PD), a movement disorder involving gait instability, slow movements, and tremor. PINK1 is a protein that plays an important role in neurons by acting as a damage sensor. Indeed, neurons harbour organelles called mitochondria, which produce energy and nutrients that are essential for neurons; to produce energy, mitochondria rely on a chain reaction that is potentially damaging if not controlled. Thus, organisms have evolved mechanisms to detect and clear damaged mitochondria, which depend on PINK1. When these mechanisms fail, the damaged mitochondria trigger a damaging inflammatory response that ultimately kill those neurons. Mitochondrial damage is a hallmark of PD, and thus we could prevent or stop PD degeneration by rescuing or increasing the activity of PINK1 in the brain. Thus, our goal is to understand how PINK1 detects damaged mitochondria and develop drugs that can boost the beneficial activity of PINK1. To achieve this goal, we will determine the 3D atomic structure of human PINK1 using X-rays, which will allow us to visualize the effect of harmful mutations and design drugs that engage specifically with PINK1. Our lab has made significant progress in the past 7 years by uncovering how PINK1 switches on its activity upon binding to mitochondria, and by discovering a class of molecules that can be used as a starting point for the development of drugs. With our collaborators at McGill and the Montreal Neurological Institute, and in partnership with the Michael J Fox Foundation, the Structural Genomics Consortium, and the private sector, we will seek to translate our finding into clinical applications.