Molecular ‘glue’ compound restores mutated parkin protein function
By removing damaged mitochondria, protein helps maintain brain cell health
A small compound that acts as a molecular glue can activate a protein that’s often mutated in people with early-onset Parkinson’s disease, a study finds.
By activating parkin, the compound enables the protein to perform its function of removing damaged mitochondria, thereby helping maintain the health of brain cells. Referred to as powerhouses, mitochondria are responsible for generating most of a cell’s energy.
“We are excited about this drug compound because we might have the possibility to develop the first cure for Parkinson’s disease, at least for a subset of patients,” Kalle Gehring, lead author of the study and a professor at McGill University, said in a university press release.
The findings of the study “Activation of parkin by a molecular glue,” which were published in Nature Communications, suggest the approach could lead to personalized treatments for younger patients with specific genetic mutations.
Parkinson’s disease typically develops later in life, with the onset of symptoms in most patients happening around age 60 or older. In about 10% to 20% of cases, the disease is diagnosed before a person reaches age 50, however. These instances are often categorized as early-onset Parkinson’s and are frequently linked to genetic mutations in different genes, including PRKN, which produces parkin.
Parkin is essential for maintaining cellular health by performing two main functions. First, it acts as a tagging enzyme, marking unnecessary or damaged proteins for removal. Second, it identifies and tags damaged mitochondria, enabling their elimination. This helps keep cells functioning properly, particularly nerve cells, because damaged mitochondria can lead to stress and contribute to neurological diseases like Parkinson’s.
Mutations in PRKNÂ cause parkin to lose its normal function, letting dysfunctional mitochondria accumulate and produce harmful substances inside cells, triggering nerve cell death.
Restoring parkin protein function
Here, McGill University researchers investigated how a molecule developed by the biotech company Biogen, called BIO-2007817, could reactivate parkin.
Researchers used advanced technology at the Canadian Light Source in Saskatchewan to study how the compound interacts with parkin in isolated cells or mitochondria. They found that BIO-2007817 acts as a molecular glue, restoring mutated parkin’s function by helping it bind to its natural activator. Specifically, it enhanced the ability of phospho-ubiquitin, a modified form of ubiquitin, to activate parkin. Ubiquitin is like a tag that cells attach to other proteins when they need to be broken down and recycled.
This way, parkin could tag damaged mitochondria for degradation and potentially prevent nerve cell damage. The researchers evaluated the interactions of this modulator at an extremely high-resolution level, letting them describe how it works in different parkin mutations and healthy states.
Activating mutated parkin helps it to perform its function and potentially offers a new avenue for future treatments.
“The hope is that one day we’ll find compounds that can treat Parkinson’s disease in general,” Gehring said.
The study underscores the increasing importance of finding better treatments for neurodegenerative diseases like Parkinson’s.
“As the population in Canada is aging and better treatments for other diseases are becoming available, neurodegenerative diseases such as Parkinson’s will be a major health concern,” Gehring said.
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