Profiling the Removal of Damaged Mitochondria in Stem Cell-Derived Brain Cells from People with Parkinson’s

Promising Outcomes of Original Grant:
Our previous work has shown that metabolic failure plays a critical role in the pathology of Parkinson’s disease (PD). A plethora of evidence from different sources — including pre-clinical models, human blood and skin cells, stem cell-derived neurons, and post-mortem human brain tissue — points to the dysfunction of mitochondria, the energy-producing “power-plants” of the cell, as central to the disease process. One key factor in this dysfunction involves the cell’s ability to remove and recycle damaged mitochondria by a process called mitophagy. It is this process of mitophagy we propose to study in greater depth. 

Objectives for Supplemental Investigation:    
The team, comprised of scientists at the Universities of Oxford and Sheffield in the UK, will come together how damaged mitochondria are degraded by mitophagy. One clue into how the process works comes from studying people with early onset PD who have rare mutations in two genes called PINK1 and PARKIN. Mutations in these genes cause the mitophagy process to fail, indicating that PINK1 and PARKIN play key roles in the normal process. This project will study the importance of mitophagy, and the role of PINK1 and PARKIN, in the dopamine-producing neurons which die in PD and in two other types of brain cells more recently thought to be important in PD, astrocytes and microglia. The team will work with stem cells generated from people with PD carrying PINK1 or PARKIN mutations, convert these stem cells in the laboratory into the different types of specialized brain cells, and examine the process of mitophagy.

Importance of This Research for the Development of a New PD Therapy:    
Many scientists think that mitophagy represents a very promising and important pathway for therapeutic targeting. Once we know more about mitophagy in PD neurons, astrocytes, and microglia we can develop new methods to repair mitophagy when it fails. Improving mitophagy in all PD cases, not just in the rare individuals with PINK1 and PARKIN mutations, should enhance the clearance of faulty mitochondria, boost the recycling of key cell components, and stimulate the production of new and healthy mitochondria.