Study reveals protein plaques in neurodegeneration function as enzymes, breaking down ATP

A new study led by Rice University's Pernilla Wittung-Stafshede has revealed that protein clumps, or plaques that clog the brain, associated with Parkinson's disease are not merely waste; they can actively drain energy from brain cells. These clumps, composed of a protein called alpha-synuclein, were found to break down adenosine triphosphate (ATP), the molecule responsible for powering nearly all cellular activities.

Published in Advanced Science Oct. 16, the research demonstrates that when ATP binds to these clumps, the protein reshapes itself to trap the molecule in a small pocket. This process causes ATP to break apart and release energy, functioning similarly to an enzyme. This unexpected finding could change scientists' understanding of the damage caused by these clumps, which are hallmarks of diseases such as Parkinson's and Alzheimer's. 

"We were astonished to see that amyloids, long thought to be inert waste, can actively cleave ATP," said Wittung-Stafshede, professor and the Charles W. Duncan Jr.-Welch Chair in Chemistry and Cancer Prevention and Research Institute of Texas Scholar. "The protein folds around ATP and essentially transforms the plaque into a molecular machine."

A new paradigm

The researchers began by creating uniform clumps of alpha-synuclein in the laboratory. They first tested whether these clumps, which contain ordered protein aggregates that adopt amyloid shapes, could break down simple chemical compounds before progressing to the actual biological substrate, ATP. Their experiments demonstrated that the protein clumps could accelerate the breakdown of ATP.

To understand this process, the research team employed advanced imaging techniques, specifically cryo-electron microscopy, collaborating with specialists in Switzerland. The images indicated that when ATP attaches to the clump, a normally loose part of the protein folds over the ATP binding site, creating a pocket that traps ATP. This pocket is lined with positive charges that facilitate the breakdown of ATP.

That folding over, or forming a lid, is what transforms a passive aggregate into a reactive enzymelike structure."

Wittung-Stafshede, Professor and the Charles W. Duncan Jr.-Welch Chair in Chemistry, Rice University

To validate their findings, the researchers altered the protein to remove the positive charges in the pocket one by one. The modified proteins still formed clumps but were unable to break down ATP or form the special pocket, highlighting the significance of that specific structure for the reaction to occur.

Implications for disease and therapeutics

This research suggests that protein clumps in the brain may cause more harm than previously believed. By breaking down ATP, these clumps could disrupt essential cellular functions, including the systems responsible for clearing them away. In this sense, the clumps might evade the body's natural cleanup mechanisms.

Given the ability of the protein clumps to change shape upon binding to specific molecules, scientists see potential for developing treatments. If small molecule drugs can lock these clumps into harmless shapes, it could help mitigate their harmful effects.

The study also implies that natural substances in the brain may influence the shapes of protein clumps in patients, possibly explaining why distinct clump shapes are found in different neurodegenerative diseases.

Improved treatments

To test if amyloid chemical reactivity occurs in mixtures of components from real brain cells, the researchers exposed extracts from neuronal cells to the protein clumps. They found that many compounds in the mixture underwent chemical changes, indicating that the clumps act on several molecules present in cells in addition to ATP.

If the findings are confirmed within living cells, this discovery could help explain why brain cells in diseases such as Alzheimer's and Parkinson's face energy shortages, DNA damage and other forms of chemical stress that ultimately lead to cell death.

As these diseases become more prevalent with an aging global population, identifying new underlying mechanisms such as this enzymatic activity could lead to improved treatments or even prevention.

"We want to learn how to stop neurodegenerative diseases at the source, directly detoxifying damaging species, instead of just treating symptoms as we do today," Wittung‑Stafshede said.

Co-authors of this study include Lukas Frey and Roland Riek from ETH Zürich and Fiamma Ayelen Buratti, Istvan Horvath, Shraddha Parate and Ranjeet Kumar from Chalmers University of Technology. Buratti is currently continuing her research with Wittung-Stafshede at Rice.

The research was supported by the Knut and Alice Wallenberg Foundation, the Swedish Research Council, the Swedish Cancer Society, the Swiss National Science Foundation and the Synapsis Foundation Switzerland.