In neurodegenerative diseases such as Parkinson’s and Alzheimer’s, clumps of misfolded proteins build up in the brain. In addition, the nerve cells typically suffer from a lack of energy. A study now shows that Parkinson’s plaques actively consume energy by breaking down the body’s own energy source ATP. However, if the researchers changed the structure of the clumped proteins, they lost the ability to bind and split ATP. This could potentially provide a new approach to treating the disease.
When proteins fold incorrectly in the brain, so-called amyloid plaques can form, i.e. clumps of pathologically modified proteins that disrupt neuronal processes and ultimately lead to the death of nerve cells. In Parkinson’s, the culprits are misfolded variants of the protein alpha-synuclein, which is actually responsible for signal transmission in the brain. Originally, these plaques typical of Parkinson’s were only considered an annoying but passive decrease in brain metabolism. However, recent studies have suggested that the protein clumps are also biologically active and can break down various substrates, at least in the laboratory.
Trapped in a bag
A team led by Lukas Frey from ETH Zurich has now shown that this degradation also affects the vital energy molecule adenosine triphosphate (ATP). “We were amazed to see that amyloids, long considered inert waste, can actively cleave ATP,” says co-author Pernilla Wittung-Stafshede from Rice University in Texas. “The protein folds around ATP and turns the plaques into molecular machines.”
Using cryo-electron microscopy, the researchers uncovered the processes that take place. Accordingly, the alpha-synuclein amyloids trap the ATP in a kind of pocket. A previously loose part of the protein folds over the bound ATP. “This folding over, i.e. the formation of a lid, is what transforms a passive aggregate into a reactive enzyme-like structure,” explains Wittung-Stafshede. Further analysis revealed that the positively charged amino acid lysine occurs frequently within the binding pocket of the protein. It holds the negatively charged ATP. The ATP is then broken down to release its energy.
Approach for new treatments?
To confirm their results, the researchers removed the positive charges in the binding pocket by replacing the positively charged lysine with the non-polar amino acid alanine. And indeed: Although the proteins modified in this way continued to clump together to form amyloid plaques, they were no longer able to bind or break down ATP. From the researchers’ perspective, these findings could point to new treatment options for Parkinson’s that aim to convert the plaques into a less harmful form.
Similar to other neurodegenerative diseases, the nerve cells in the brains of Parkinson’s patients typically suffer from a lack of energy. The current results could now at least partially explain how this comes about. Even if the observed ATP depletion rates are low, they could be enough to create a local energy deficiency – enough to, among other things, paralyze the brain’s cleaning systems that are actually responsible for breaking down the plaques. “This would essentially make the amyloids ‘invisible’ to rescue and/or degradation mechanisms and represents a completely new chemical concept in the field of amyloid diseases,” write Frey and his team.
However, it is still unclear whether the effects discovered in the laboratory also play a relevant role in the living brain. The researchers want to clarify this question in future studies. “We want to learn how to stop neurodegenerative diseases at the source by directly detoxifying harmful species instead of just treating the symptoms as we do today,” says Wittung-Stafshede.
Source: Lukas Frey (ETH Zurich, Switzerland) et al., Advanced Science, doi: 10.1002/advs.202508441