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Parkinson’s disease is a progressive neurodegenerative disease of the central nervous system. Symptoms include a loss of motor control leading to tremors, rigidity and difficulty with balance and movement, and can progress to mood swings, psychosis and dementia. At least 1 % of adults over the age of 60 are affected, and while treatments exist, there is no cure.
The causes of Parkinson’s continue to elude researchers, but decades of research have provided some important clues. Among them is the role of proteins – specifically alpha-synuclein. This neuronal protein plays an important role in healthy brain function, but is susceptible to misfolding, a process that sees deformed proteins form aggregations in cells.
Although there is no consensus, one theory suggests that the passing of these toxic clumps from one neuron to another is what causes Parkinson’s disease to progress. Work by the SYN-CHARGE project, which was funded by the Marie Skłodowska-Curie Actions programme, has identified a new way these misfolded proteins might be targeted.
“Misfolded proteins can poison the healthy nerve cells that keep our brain functioning,” says Birthe B. Kragelund, a professor of Biomolecular Sciences at the University of Copenhagen in Denmark. “This in turn causes the neurons that produce dopamine to die, triggering such hallmark Parkinson’s symptoms as motor and cognitive deficits that worsen over time.”
As Kragelund notes, dopamine is a chemical messenger responsible for conveying information from neuron to neuron. It’s also responsible for making sure that movements are smooth and not jerky or too rigid, as seen in Parkinson’s.
Holding a mirror up to disordered protein complexes
The project primarily focused its research on enantiomers – two compounds that contain all the same molecular components but are mirror images of each other.
“Think of enantiomers as your left and right hands,” explains Kragelund, who served as the project coordinator. “Although both hands reflect features that are similar to each other, they are clearly not the same.”
Proteins (and their smaller cousins, peptides) are made up of hundreds or even thousands of amino acids, bound together to form long chains. Naturally occurring proteins, including alpha-synuclein, are composed of ‘left-handed’ or laevorotatory (L) amino acids. However, amino acids have a ‘right-handed’ version, known as the dextrorotatory (D) form. Joined together, these D-amino acids can produce a mirror image peptide chain – rare in nature, but feasible to produce in the laboratory.
Kragelund’s team discovered that these D-peptides have the potential to bind with misfolded L-alpha-synuclein proteins. “Well-structured proteins aren’t able to interact with the mirror image of their binding partner, as the proteins would not fit together, but disordered proteins can,” remarks Estella Newcombe, the project’s lead researcher and an assistant professor at the University of Copenhagen.
Targeting Parkinson’s disease using D-peptides
The finding contradicts preconceived notions about the ability of mirror image proteins to interact with their inverted partner. It opens the door to using enantiomers as a means of targeting the disordered proteins that are thought to cause Parkinson’s disease.
“Peptide-based therapies are increasingly being studied, and our work positions D-peptides as an interesting option as they are not readily degraded by the proteolytic activity of biological systems, possibly making for a longer-lasting treatment,” notes Newcombe.
The key is figuring out the right D-peptide to interact with alpha-synuclein. “If we can find a binding partner for disordered alpha-synuclein that stops it from forming aggregates, or clumps, we can make a D-peptide version of this binding partner that is much more stable in the body,” adds Newcombe. “Theoretically, less aggregation would mean healthier neurons and less disease pathology.”
She concludes: “By showing that L- and D-proteins can interact in certain conditions, we have pushed the boundaries of what we know about protein biochemistry and laid the foundation for researching possible new therapies for treating Parkinson’s disease.” The work could also inform the treatment of similar diseases thought to be driven by protein misfolding, such as Alzheimer’s and Huntington’s.