Study reveals potential role of polyphosphates in neurodegenerative diseases

A University of Michigan-led study has provided powerful evidence that could solve a fundamental mystery in the composition of fibrils involved in Alzheimer's disease, Parkinson's disease and other neurodegenerative diseases.

We have long seen these fibrillar structures in the brains of patients. But the question is, what do these fibrils do? What is their role in disease? And most importantly, if they are the cause of these devastating diseases, can we do anything to get rid of them?”

Ursula Jacob, senior author of the new study

Although this new discovery does not definitively answer these questions, it may provide a missing piece of the puzzle for researchers seeking to understand how these diseases work at the molecular level. be. And given the lack of treatment options for Alzheimer's disease, the need for this deeper understanding is clear, Jacob said.

The Food and Drug Administration has approved three new drugs for Alzheimer's disease since 2021, but that preceded 17 years without new approvals despite hundreds of clinical trials. (more than 100 drug candidates are currently being evaluated).

“Given all these clinical trial failures, there must still be some important pieces of this puzzle missing,” says Jacob, a professor in UM's Department of Molecular, Cellular, and Developmental Biology. “Therefore, the basic research that we and many others around the world are doing is sorely needed to treat, much less eliminate, these terrible diseases.”

mysterious density

Researchers have long known that fibrils, tiny curly hairs assembled from tiny invisible components called amyloid proteins, are associated with many neurodegenerative diseases. However, important questions remain about how these structures accumulate in the body and how they influence the progression of these diseases.

Our understanding of fibrils continues to evolve as scientists introduce new tools and methods to examine the structure more closely. One of those innovations is known as cryo-electron microscopy (Cryo-EM).

“This is a very sophisticated technology,” Jacob said. “With this, you can see in great detail what these fibrils look like.”

In 2020, an international team led by researchers from Cambridge used cryo-EM to discover mysterious clumps inside fibrils recovered from patients with a neurodegenerative disease called multiple system atrophy.

Although researchers have been able to characterize the fibrils down to the individual amino acid units that make up the larger protein structure, there remains an unknown substance running along the length of the fibrils. Ta.

“It was in the middle of the fibril, but they had no idea what it was,” Jacob said. “They called it 'mysterious density.'”

Now, Jacob and her colleagues have shown that a ubiquitous biological polymer called polyphosphate may be that mysterious density.

The research team reported their findings in a journal PLOS Biology.

New science, ancient molecules

Polyphosphate is a molecule that is present in all living things today and has been used by living things throughout evolution, Jacob said. Thanks to laboratory experiments conducted by Jakob and other scientists, it has also been linked to several neurodegenerative diseases.

For example, her team showed that polyphosphate helps stabilize fibrils, reducing their potential for disruption to neurons cultured in the lab. Other researchers have shown that the amount of polyphosphate in the brains of rats decreases with age.

These results suggest that polyphosphates may be important in protecting humans from neurodegenerative diseases. Still, scientists lacked direct evidence for this.

“You can do a lot of things with test tubes,” Jacob says. “The question is, which ones are truly relevant to the human body?”

However, the human brain is an incredibly complex environment. Scientists have not yet designed experiments that could definitively elucidate the role of polyphosphate.

But thanks to previous research, scientists now have the exact 3D structure of real fibrils in humans. By creating computer models of these structures, Jacob and her team were able to run simulations that asked how polyphosphate interacts with fibrils. They found that it was very well suited to the density of the mystery.

Next, they went a step further and tweaked the fibril's structure, changing the amino acids at the cryptic density boundary. When they tested these fibril mutants, they found that polyphosphate was no longer associated with the fibril mutants and no longer protected neurons from fibril toxicity.

“It's just not technically possible because we can't extract polyphosphate from patient-derived fibrils, so we can't say for certain that it really is the mysterious density,” Jacob said. “What we can say is that we have very good evidence that the cryptic density is compatible with polyphosphates.”

Their research led to the hypothesis that finding ways to maintain adequate polyphosphate levels in the brain could slow the progression of neurodegenerative diseases. But proving it will still require a significant investment of time and money, Jacob said, and will likely unravel new mysteries in the process.

“I would say we are still at a very early stage. It has only recently become clear that these fibrils have additional components,” she said. “Sometimes these components play a big role, and sometimes they don't play a role at all. But only when the pieces of the puzzle fall into place will we successfully fight these highly devastating diseases.” I hope you can.”

The study was supported by the National Institutes of Health and included collaborators at the Howard Hughes Medical Institute, Manipal Academy of Higher Education, and the University of California, San Francisco.

The study's first authors were Pavithra Mahadevan, a graduate student in Jacob's lab, and Philipp Hüttemann, who conducted the research as an undergraduate at the Massachusetts Institute of Technology.