A groundbreaking study from Rice University, led by Pernilla Wittung-Stafshede, has unveiled that protein clumps associated with Parkinson’s disease actively deplete energy from brain cells. These clumps, composed of the protein alpha-synuclein, have been found to break down adenosine triphosphate (ATP), a molecule essential for cellular energy. The research, published on October 16 in Advanced Science, challenges previous assumptions about these clumps being mere cellular waste.
The study reveals that when ATP binds to these protein clumps, the protein alters its shape to trap ATP in a pocket, causing it to break apart and release energy, functioning similarly to an enzyme. This discovery could significantly alter the scientific community’s understanding of the damage these clumps inflict, which are also hallmarks of other neurodegenerative diseases like Alzheimer’s.
Revolutionizing Understanding of Protein Clumps
Wittung-Stafshede, a professor and the Charles W. Duncan Jr.-Welch Chair in Chemistry, expressed surprise at the findings.
“We were astonished to see that amyloids, long thought to be inert waste, can actively cleave ATP,”
she stated. The research team began by creating uniform clumps of alpha-synuclein in the lab to test their ability to break down ATP.
Using advanced imaging techniques, such as cryo-electron microscopy, the team collaborated with Swiss specialists to visualize the process. They discovered that when ATP attaches to the clump, a part of the protein folds over the ATP binding site, creating a pocket lined with positive charges that facilitate ATP breakdown.
“That folding over, or forming a lid, is what transforms a passive aggregate into a reactive enzymelike structure,”
Wittung-Stafshede explained.
Potential Therapeutic Implications
This discovery suggests that protein clumps in the brain may be more harmful than previously thought. By breaking down ATP, these clumps could disrupt vital cellular functions, including those responsible for their clearance, potentially allowing them to evade the body’s natural defenses.
Scientists are now considering the potential for developing treatments that could lock these clumps into harmless shapes using small molecule drugs. This approach could mitigate their harmful effects, offering a new avenue for therapeutic development.
The study also hints that natural substances in the brain might influence the shapes of protein clumps in patients, possibly explaining the distinct clump shapes observed in various neurodegenerative diseases.
Broader Implications for Neurodegenerative Diseases
To further explore the chemical reactivity of amyloids, the researchers exposed extracts from neuronal cells to the protein clumps. They observed that many compounds underwent chemical changes, indicating that the clumps act on several cellular molecules in addition to ATP.
If these findings are confirmed in living cells, they could help explain why brain cells in diseases like Alzheimer’s and Parkinson’s face energy shortages and other forms of chemical stress leading to cell death. As these diseases become more prevalent with an aging population, identifying new mechanisms like this enzymatic activity could lead to improved treatments or even prevention strategies.
Wittung-Stafshede emphasized the importance of this research, stating,
“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.”
The study was a collaborative effort with co-authors from ETH Zürich and Chalmers University of Technology, with support from several prestigious foundations, including the Knut and Alice Wallenberg Foundation and the Swiss National Science Foundation.
