In a study published in nature communications, a team led by Krembil Brain Institute senior scientists Drs. Lorraine Kalia and Suneil Kalia, and University of Toronto (U of T) Professor Dr. Philip M. Kim, identified a protein-protein interaction that contributes to Parkinson’s disease.
In the disease, a protein called ?-synuclein (a-syn) accumulates in the brain and leads to cell death. Much of the research is currently focused on the removal of a-syn with antibodies or the use of small molecules to prevent a-syn from being added. In this study, the researchers took an alternative approach by looking for protein-protein interactions that might promote a-syn accumulation in Parkinson’s disease.
Protein-protein interactions govern virtually all of the inner workings of the cell, including the breakdown of disease-causing proteins. Inhibiting certain interactions has become 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 interrupt it can be a painstaking and incredibly time-consuming process,” explains Dr. Lorraine Kalia, who is also a UHN staff neurologist and a scientist at U of T’s Tanz. Center for Research in Neurodegenerative Diseases, at the Temerty School of Medicine.
“We all started out a bit skeptical that we would have something useful in the end, so the fact that we have something that warrants more work is way more than we expected.”
According to Dr. Kim, the team took the reverse approach to speed discovery of potential therapies. “We developed a platform to examine molecules called peptide motifs (short chains of amino acids that can alter protein-protein interactions) for their ability to protect cells from a-syn. Once we identified candidate peptides, we determined which protein-protein interactions to which they aim”.
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 the ‘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,” explains Dr. Lorraine Kalia. “We found that a-syn interacts with a protein within ESCRT-III, CHMP2B, to inhibit this pathway, thus preventing its own destruction.”
“We were impressed that the platform worked,” he adds. “But I think what was more interesting is that by doing this type of evaluation, we were able to find an interaction that hadn’t really been previously characterized, and we also found a pathway that hasn’t been addressed yet.”
According to Dr. Suneil Kalia, 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 elimination pathways.
“We tested the peptide in multiple experimental models of Parkinson’s disease, and consistently found that it restored endolysosomal function, promoted a-syn clearance, and prevented cell death,” he said.
These findings indicate that the α-syn-CHMP2B interaction is a potential therapeutic target for the disease, as well as for other conditions involving an accumulation of α-syn, such as Lewy body dementia.
The next steps in this research are to clarify exactly how a-syn and CHMP2B interact to disrupt endolysosomal activity. Ongoing studies are also determining the best approach to deliver potential therapies to the brain.
“This research is still in its early stages; more work is definitely needed to translate this peptide into a viable treatment,” warns Dr. Lorraine Kalia. “However, 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 done this study in a silo,” says Dr. Suneil Kalia. “The endolysosomal pathway is poorly explored, so it was not an obvious place to look for potential disease-related protein-protein interactions. Dr. Kim’s screening platform was instrumental in pointing us in the right direction.”
“It’s remarkable to see this platform, which we initially used to find potential cancer therapies, lead to breakthroughs in brain research. The pathways cells use to stay healthy are fundamentally very similar in all tissues, so the insights What we get about one organ system or disease could have important implications in other contexts,” says Dr. Kim.
“This is our first collaboration with Dr. Kim and it has been productive with a lot of synergy,” says Dr. Lorraine Kalia. “Looking at technologies that are being used in other fields and applying them to our own field, we hope this will accelerate Parkinson’s research.”
She adds: “It’s really a whole new science and whole new targets that haven’t been a focus for Parkinson’s drug development. We hope this will change the landscape for treating this disease, which needs new therapies.”