Department of Pharmacology & Therapeutics, McGill University
New Investigator Award: $90,000 over two years
Structural basis of PINK1 kinase activation
Before targeted research into the prevention or treatment of Parkinson’s disease can succeed, that research has to rely on a foundation of basic, curiosity-driven science. At McGill University, structural biologist Jean-Francois Trempe undertakes that basic research into the structure and shape of PINK1, a protein that plays a critical role in familial forms of Parkinson’s disease.
Brain cells need PINK1 to stay healthy, Trempe says. In brain cells, PINK1 attaches itself to mitochondria, the tiny organs within cells that produce energy, and monitors their health. When mitochondria become damaged or unhealthy, PINK1 signals other proteins, including one called Parkin, to repair the damage, or clear out the damaged mitochondria if they can’t be repaired.
If PINK1 is misshapen or damaged (a process called genetic mutation), then it won’t signal Parkin correctly. If PINK1 can’t tell Parkin to do its job, that miscommunication can cause brain cells that produce dopamine to die. Dopamine is a brain chemical that regulates movement. If dopamine-producing cells die, the result is Parkinson’s disease.
What researchers like Trempe don’t know is the exact structure, or shape, of the PINK1 protein. Knowing the shape is important, because that knowledge could eventually help other researchers create a drug or a type of genetic therapy to recover the function of the damaged protein. Trempe is creating a synthetic model of PINK1, to determine its structure. He will then compare it to a mutated model of the protein, to pinpoint exactly where damage or mutations have changed the protein’s shape. Knowing PINK1’s shape will help drug developers create new molecules that attach to the damaged protein and repair it in exactly the right spot – just like a puzzle piece.
“No one has done this before for PINK1,” says Trempe. “History tells us that whenever we understand the structure of a molecule, it gives us so many ideas.”
Trempe, whose great-uncle had Parkinson’s, wants to solve the puzzle of Parkinson’s through basic understanding about the way the disease works. “That has to come from curiosity-driven science,” he says.