Potential New Therapeutic Target Spotted In Parkinson’s Disease

A team of researchers from the Krembil Brain Institute (KBI) and the University of Toronto have identified a protein-protein interaction that contributes to Parkinson’s disease.

In a study published in Nature Communications, KBI scientists Lorraine Kalia and Suneil Kalia and U of T researcher Philip M. Kim examined a protein called alpha-synuclein (a-syn) that accumulates in the brain in patients with Parkinson’s and leads to cell death.

Much research is currently focused on clearing a-syn with antibodies or using small molecules to prevent a-syn from aggregating. In their study, the researchers took an alternate approach by looking for protein-protein interactions that may be promoting the accumulation of a-syn in Parkinson’s disease.

Protein-protein interactions govern most inner workings of the cell, including breaking down disease-causing proteins. Inhibiting certain interactions has emerged as a promising approach to treat diseases such as stroke and cancer.

“Identifying a particular interaction that contributes to a disease, and then finding ways to disrupt it, can be a painstaking and incredibly slow process,” says Lorraine Kalia, who is also a staff neurologist at University Health Network, a scientist at U of T’s Tanz Centre for Research in Neurodegenerative Diseases and an assistant professor in the division of neurology and in the department of laboratory medicine and pathobiology in the Temerty Faculty of Medicine.

“We all started out a bit skeptical that we would have something useful at the end, and so the fact that we do have something that warrants further work is much more than we anticipated.”

Kim, who is a professor in U of T’s Donnelly Centre for Cellular and Biomolecular Research and in the department of molecular genetics in the Temerty Faculty of Medicine, notes the team took an approach they hoped would expedite the discovery of potential therapies.

“We developed a platform to screen molecules called peptide motifs – short strings of amino acids that can disrupt protein-protein interactions – for their ability to protect cells from a-syn,” Kim says. “Once we identified candidate peptides, we determined which protein-protein interactions they target.”

Through this approach, the team identified a peptide that reduced a-syn levels in cells by disrupting the interaction between a-syn and a protein subunit of the cellular machinery called “endosomal sorting complex required for transport III” (ESCRT-III).

“ESCRT-III is a component of a pathway that cells use to break down proteins, called the endolysosomal pathway. We discovered that a-syn interacts with a protein within ESCRT-III – CHMP2B – to inhibit this pathway, thereby preventing its own destruction,” Lorraine Kalia says.

“We were impressed that the platform worked. But I think what was more interesting is that by doing this kind of screening, we were able to find an interaction that was really not previously characterized, and we also found a pathway that’s not yet been targeted for therapeutics.”

Once the group identified this interaction, they confirmed that they could use their peptide to disrupt it – preventing a-syn from evading the cell’s natural clearance pathways, notes Suneil Kalia, who holds the R.R. Tasker Chair in Stereotactic and Functional Neurosurgery at UHN and is an associate professor in the division of neurosurgery in the Temerty Faculty of Medicine.

“We tested the peptide in multiple experimental models of Parkinson’s disease, and we consistently found that it restored endolysosomal function, promoted a-syn clearance and prevented cell death,” he says.

These findings indicate that the a-syn-CHMP2B interaction is a potential therapeutic target for the disease, as well as other conditions that involve a buildup of a-syn, such as dementia with Lewy bodies (another disease associated with abnormal deposits of a-syn in the brain).

The next steps for this research are to clarify exactly how a-syn and CHMP2B interact to disrupt endolysosomal activity. Ongoing studies are also determining the best approach for delivering potential therapeutics to the brain.

“This research is still in its early stages – more work is definitely needed to translate this peptide into a viable therapeutic,” cautions Lorraine Kalia. “Nonetheless, our findings are very exciting because they suggest a new avenue for developing treatments for Parkinson’s disease and other neurodegenerative conditions.”

This study also highlights the value of multidisciplinary collaborations in health research.

“We simply could not have conducted this study in a silo. The endolysosomal pathway is underexplored, so it was not an obvious place to look for potential disease-related protein-protein interactions. Dr. Kim’s screening platform was critical for pointing us in the right direction,” Suneil Kalia points out.

“It is really extraordinary to see this platform – which we initially used to find potential therapeutics for cancer – yielding advances in brain research. The pathways that cells use to stay healthy are fundamentally very similar across tissues, so the insights that we gain about one organ system or disease could have important implications in other contexts,” Kim says.

“It’s really brand-new science and targets that haven’t been a focus for drug development for Parkinson’s,” Lorraine Kalia adds. “We hope this changes the landscape for treatment of this disease, which is so in need of new therapies.”

The research was supported by the Canadian Institutes of Health Research, the Michael J. Fox Foundation for Parkinson’s Research, Parkinson’s UK, the Canada Foundation for Innovation, the Ontario Research Fund, the Krembil Research Institute and the UHN Foundation.