Integrative screens to uncover novel regulators of SNCA expression in the context of Parkinson’s disease pathogenesis

A buildup of the alpha-synuclein protein in brain cells has become the hallmark of Parkinson’s. Recently, researchers have discovered that having even slightly more of this protein in the brain than is normal can affect people’s risk of developing the disease.

“When you have only mild elevation of alpha-synuclein over the long-term, that increases the chance of getting Parkinson’s,” says Konrad Ricke, a postdoctoral fellow at the University of Ottawa.

If scientists could discover some way of lowering the amount of alpha-synuclein in brain cells that produce dopamine, the key chemical involved in Parkinson’s, they might be able to prevent people from developing Parkinson’s altogether.

That’s why Ricke, a neuroscientist, is searching for ways to control levels of alpha-synuclein, by finding other proteins that interact with alpha-synuclein’s gene.

“There may be a huge, unknown group of alpha-synuclein regulators,” Ricke says. “The main goal of my project is to identify them.”

Ricke uses CRISPR, a powerful tool for editing DNA and modifying the function of genes, to screen thousands of proteins simultaneously to see which are connected to alpha-synuclein.

He’s also screening potential locations, or sites, in the alpha-synuclein gene itself to see where the other proteins could bind (connect) and affect the activity of the alpha-synuclein gene. If he can identify proteins that regulate the gene, that could influence the amount of the alpha-synuclein protein that gene expresses.

Once Ricke finds these proteins and their binding sites, he’ll have identified potential targets for new drugs or gene editing therapies.

Eventually, altering one or more of the proteins or blocking the binding sites could reduce the amount of alpha-synuclein in brain cells – enough to eliminate that risk factor for developing Parkinson’s.

Measuring these protein regulators could also become a biomarker to alert people about their Parkinson’s risk, Ricke says.

His work will “either help you to protect yourself from Parkinson’s, potentially, or it could tell you that you are at high risk to develop Parkinson’s at 60 or 70 years old and you have to prepare yourself for that,” he says.

When he was in high school, Ricke became fascinated by the way brain cells communicate with each other. That fascination led to his research career, and the realization that the loss of a small population of cells, like the dopamine neurons involved in Parkinson’s, can have a devastating effect on someone’s life.

He hopes his work will ultimately shape new treatment strategies to get around the limits of the current therapies for Parkinson’s.