Protein aggregates are the hallmark of a number of neurodegenerative diseases. New research, published in the journal PLOS Biology, examines a human enzyme that unravels these disruptive plaques.
Neurodegenerative diseases already affect millions of people in the United States. They tend to strike in middle to later life, and, because the population is starting to live longer, the number of cases is set to rise.
By some estimates, in 30 years, there will be 12 million people in the U.S. living with a neurodegenerative condition.
These diseases include Alzheimer’s, Parkinson’s, Lou Gehrig’s disease (or amyotrophic lateral sclerosis), and Huntington’s disease. Characterized by a slow deterioration of neurons, neurodegenerative conditions gradually degrade emotional, cognitive, and memory functions.
Worryingly, none of these conditions have a cure. In general, treatment only focuses on addressing symptoms and slowing the progression of the disease. Consequently, many researchers are investigating potential ways to tackle them.
Many neurodegenerative conditions are known to involve a buildup of amyloid-forming proteins. For instance, the brains of people with Alzheimer’s disease develop aggregates of tau proteins, and those of people with Parkinson’s disease develop collections of alpha-synuclein.
In short, amyloids are proteins that become abnormally folded, clump together, and form insoluble oligomers and fibrils.
Amyloids, proline, and CyP40
The abnormal protein aggregations in neurodegenerative diseases all contain an amino acid called proline. This protein’s unique structure causes the amino acid chains to bend, thereby stacking regions of the protein together and promoting the formation of amyloid.
Recently, a team of scientists from the University of South Florida in Tampa investigated the potential of a human enzyme to interfere with the buildup of protein aggregates in neurodegenerative conditions. Led by professors Jeremy Baker, Laura Blair, and Chad Dickey, the researchers focused on the enzyme cyclophilin 40 (CyP40).
During normal protein folding, CyP40 acts as a chaperone – that is, it grabs and steers prolines to their destination, creating their distinct chain-bending formation and assisting in the development of amyloids. Specifically, prolines are found in so-called beta-turns, a hallmark of aggregates in many neurodegenerative conditions.
Although CyP40 seems to be part of the problem, as with most enzymes, it can also work in reverse; it can unbend the proteins by undoing the beta-turns, thereby unfolding the aggregates.
Using a mouse model of Alzheimer’s disease, the team found that CyP40 could reduce the buildup of aggregated tau, making it more soluble. This prevented the degeneration of neurons and reduced some of the negative cognitive consequences. Similarly, CyP40 broke down alpha-synuclein, the Parkinson’s aggregate.
Previous work has shown that this enzyme can break down aggregates in vitro, but these findings are the first time that CyP40 has been shown to disaggregate amyloid proteins in an animal model of neurodegenerative disease.
How does CyP40 work?
At this stage, it is not entirely clear how CyP40 breaks down amyloid proteins, but the authors offer two possible explanations. Either it binds directly to proline and unfolds the aggregates, or it binds to the protein before it aggregates, preventing it from clumping in the future.
The importance of these findings is clear. Although there will need to be more work done to understand the mechanisms at work, having a tool to unlock the misfolded proteins could be a game-changer in the treatment of neurodegenerative conditions.
CyP40 is not the only enzyme that could be of potential use. As Blair explains, “The finding that Cyp40 can untangle clumps of tau and alpha-synuclein suggests that it, or one of the more than 40 other human proteins with similar activity, may have a role to play in treating neurodegenerative disease.”