Study reveals protein-protein interactions that contribute to Parkinson’s disease

In a study published in Nature Communications, a team led by senior scientist at the Crenville Brain Institute, Ph.D. Lorraine Kalia, her Suneil Kalia, and her Dr. Philip M. Kim, professor at the University of Toronto (University of T), have identified protein-protein interactions that contribute to Parkinson’s disease.

In this disease, a protein called alpha-synuclein (a-syn) accumulates in the brain and causes cell death. Much research is currently focused on the removal of a-syn by antibodies or the use of small molecules to prevent a-syn aggregation. In this study, the researchers took a different approach, looking for protein-protein interactions that may be driving a-syn accumulation in Parkinson’s disease.

Protein-protein interactions govern nearly all of the inner workings of the cell, including the breakdown of disease-causing proteins. Inhibiting specific interactions has emerged as a promising approach for treating diseases such as stroke and cancer.

“Identifying the specific interactions that contribute to disease and finding ways to disrupt them can be an arduous and incredibly slow process,” said a UHN staff neurologist. explains Lorraine Kalia, Ph.D., a scientist at Tanz University. Neurodegenerative Disease Research Center, Temati School of Medicine.

“We were all a little skeptical that we would end up with anything useful.

According to Dr. Kim, the team took the opposite approach to expedite the discovery of potential treatments. “We have developed a platform for screening molecules called peptide motifs, which are short strings of amino acids that can disrupt protein-protein interactions. They protect cells from a-syn. It’s about the ability.Once we identified the candidate peptides, we decided which protein-protein interactions they were targeting.”

Through this approach, the research team has determined that intracellular identified peptides that reduced a-syn levels of

ESCRT-III is a component of a pathway that cells use to degrade proteins, called the endolysosomal pathway. We found that a-syn interacts with proteins within her ESCRT-III-;CHMP2B-; to inhibit this pathway and thereby prevent its own destruction. “

Dr. Lorraine Kalia, UHN Staff Neurologist

“I was impressed with how the platform worked,” she adds. “But more interestingly, doing this kind of screen allowed us to find previously uncharacterized interactions, as well as pathways that have not yet been targeted for therapeutics.”

After the group identified this interaction, they confirmed that they could use peptides to disrupt it and prevent a-syn from circumventing the cell’s natural clearance pathways, according to Dr. Suneil Kalia. bottom.

“When we tested the peptide in multiple models of Parkinson’s disease, we consistently found that it restored endolysosomal function, enhanced a-syn clearance, and prevented cell death.

These findings indicate that the a-syn-CHMP2B interaction is a potential therapeutic target for this disease and other conditions involving a-syn accumulation, such as dementia with Lewy bodies.

The next step in this study is to clarify exactly how a-syn and CHMP2B interact to disrupt endolysosomal activity. Ongoing research is also determining the best approaches to deliver potential therapeutics to the brain.

“This research is still in its early stages. Much more work is needed to transform this peptide into a viable therapeutic,” warns Dr. Lorraine Kalia. “Nevertheless, our findings are very exciting because they suggest new avenues for developing treatments for Parkinson’s disease and other neurodegenerative conditions.”

This study also highlights the value of interdisciplinary collaboration in health research.

“We couldn’t do this research in a silo,” said Dr. Suneil Kalia. “The endolysosomal pathway has not been an obvious place to look for possible disease-relevant protein-protein interactions because it is understudied. Dr. Kim’s screening platform points us in the right direction.” It was important for

“It’s amazing to see this platform. Initially we used it to find potential cures for cancer, but it has made progress in researching the brain. Because the pathways we use are fundamentally very similar across tissues, the insights we gain in one organ system or disease may have important implications in other contexts.” says Dr. Kim.

“This was our first collaboration with Dr. Kim, and it was a lot of synergistic and productive,” says Dr. Lorraine Calliah. I hope that applying it to my field will accelerate research into Parkinson’s disease.”

She adds: “What has not been the focus of drug development for Parkinson’s disease is an entirely new science, an entirely new target, which will change the landscape of treatment for this disease, where new therapies are sorely needed. I hope.”