Causes - Dr. Jungwoo Yang - Helping cells cope with stress

Dr. Jungwoo Yang
University of Ottawa
Basic Research Fellowship
$100,000 over two years

Parkinson’s disease, LRRK2, Endoplasmic Reticulum stress, PKR-like endoplasmic reticulum kinase (PERK) and unfolded protein response

Proteins are essential to keeping our bodies’ billions of cells alive and healthy. In order for various proteins to go about their business, they must be folded into specific shapes to interact with other biochemical agents. When that folding fails to occur, or proteins fold themselves into the wrong shapes, trouble arises.

Jungwoo Yang studies that trouble, which may be among the most fundamental causes of Parkinson’s Disease. Yang, a doctoral student at the University of Alberta, is examining a stress response that occurs in a part of the cell known as the endoplasmic reticulum, where tube-like structures deliver proteins to other parts of the cell. When too many of these proteins are unfolded or misfolded, the resulting stress activates an unfolded protein response (UPR) that can damage cells. This response includes a process called phosphorylation of PERK, the addition of phosphates that can eventually poison a cell and kill it.

“I already knew that this process was happening of higher phosphorylated PERK in people with Parkinson’s disease,” says Yang.

PERK is the enzyme at the heart of this fatal cascade. Yang began his research by studying how the genetic activation of PERK decides the fate of cells during the stress response within the endoplasmic reticulum. The process resembles the way in which prions cause misfolding of proteins within brain cells, creating the condition known as mad cow disease. Yang suspects a similar culprit might be at work in causing changes within PERK.

Now, thanks to support from Parkinson Canada, Yang is exploring the possibility that inhibiting PERK’s activity could prevent it from starting the chain of events that kills cells, which in turn could prevent the neurodegeneration seen in Parkinson’s, Alzheimer’s disease or amyotrophic lateral sclerosis (ALS). Yang will test this hypothesis by confirming the mechanism in mice.

“We’re going to inject them with endoplasmic reticulum stress inducers and observe the effects of P-PERK inhibitor,” says Yang. “If we see something that looks like Parkinson’s and inhibits or delays Parkinson’s by using P-PERK inhibitor, that will confirm our model.”

Eventually, Yang hopes his research will open the way to a drug or gene therapy that could treat or prevent Parkinson‘s disease by preventing the stress response that damages or kills brain cells.

“If we can inhibit the activity of PERK, it will make a crucial contribution to protecting patients from neurodegeneration. Our study will validate a target mechanism for doing just that as we develop future treatment strategies.”