Understanding a critical protein at the atomic level

Molecular determinants of alpha-synuclein misfolding in cells

Dr. Vladimir Ladizhansky
University of Guelph
Pilot Project Grant
$50,000 over 1 year

Understanding the way proteins interact, with each other and within brain cells, is key to figuring out how Parkinson’s disease begins, and discovering ways to stop or prevent it.

At the University of Guelph, Professor Vladimir Ladizhansky, a biophysicist, is interested in the way a protein called alpha-synuclein interacts with cell membranes. He’s using nuclear magnetic resonance as an imaging technique to examine that process at the atomic level.

Researchers already know that this unusual protein lies at the heart of Parkinson’s disease. Toxic clumps of misshapen alpha-synuclein accumulate in the brain cells that produce dopamine, a signalling chemical that directs our body’s motor function.

These clumps, also known as fibrils, kill the dopamine brain cells, causing Parkinson’s motor symptoms like tremors, shakiness and rigidity.

Ladizhansky believes the interaction between alpha-synuclein and cell membranes can modulate the clumping process within neurons. In some cases, the interaction promotes the formation of these clumps—but in other places, the interaction can help to dissolve them.

“We’re trying to understand what exactly controls that process—under what conditions cell membranes dissolve those fibrils and under what conditions they promote them,” Ladizhansky says.

“There’s a long path between what we do, which is fundamental structural biology, to medical applications.”

Nuclear magnetic resonance allows him to observe the process as it happens, at the atomic level within cells.

“If we understand better how things work, we can hope to control them better— maybe find a way to inhibit the production of the fibrils, or dissolve them,” he says.

Examining this process is challenging, Ladizhansky says, because alpha-synuclein doesn’t behave the way most other proteins do. Rather than having a well-defined three-dimensional structure that is easy to model, as most proteins do, alpha-synuclein is what Ladizhansky calls “intrinsically disordered.” It has no particular structure on its own, but changes shape depending upon other proteins or molecules it interacts with.

Ladizhansky is focused on gaining fundamental knowledge from his research, not on its applications.

“There’s a long path between what we do, which is fundamental structural biology, and to medical applications.”

As a child in Russia, Ladizhansky was inspired to follow Nobel laureate Lev Landau into physics when he read a book about the famous co-founder of the quantum theory of condensed matter.

Like other fundamental researchers, Ladizhansky believes the key to any later developments in treating Parkinson’s is to first understand how and why the disease is happening.

“You cannot do anything without that knowledge,” he says.