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University of Michigan researchers uncover polyphosphate as a key component in neurodegenerative disease fibrils, potentially offering new treatment insights.
A breakthrough study from the University of Michigan may hold the key to unlocking the mystery surrounding the fibrils involved in Alzheimer’s, Parkinson’s, and other neurodegenerative diseases. The research team has identified polyphosphate as a likely “mystery density” within these fibrils, offering a fresh perspective on their role in disease progression. This discovery may have profound implications for understanding these disorders at a molecular level and, potentially, for developing new treatment strategies. However, further research is needed to confirm polyphosphate’s protective effects in the human brain.
The study, led by Ursula Jakob, a professor in the U-M Department of Molecular, Cellular, and Developmental Biology, aims to unravel a longstanding enigma. “We’ve seen that patients have these fibril structures in their brains for a long time now,” Jakob explained. “But the question is, what do these fibrils do? What is their role in disease? And, most importantly, can we do something to get rid of them if they are responsible for these devastating diseases?”
Although the study doesn’t yet provide all the answers, it offers a crucial piece of the puzzle in understanding how these diseases develop at the molecular level. Jakob emphasized the importance of this research, particularly given the limited progress in developing treatments for Alzheimer’s. Since 2021, the FDA has approved three new drugs for Alzheimer’s disease, but prior to that, there had been a 17-year drought in new drug approvals, despite numerous clinical trials.
“Given all these unsuccessful clinical trials, we must still be missing some important pieces of this puzzle,” Jakob said. “So the fundamental research that we and many others around the world are doing is critically necessary if we ever want to treat, much less eliminate, these terrible diseases.”
The Mystery Density:
For years, scientists have been aware of fibrils—tiny tendrils made up of amyloid proteins—that are linked to several neurodegenerative diseases. Yet, many questions remain about how these fibrils form and how they contribute to the progression of these conditions.
Recent advancements, particularly the development of cryogenic electron microscopy (cryo-EM), have enabled researchers to study fibrils in unprecedented detail. In 2020, an international team using cryo-EM discovered an unknown material inside the fibrils recovered from patients with multiple system atrophy, a neurodegenerative disease. This material, which they dubbed the “mystery density,” remained unidentified until now.
Jakob and her team have now presented compelling evidence suggesting that polyphosphate—a biological polymer found in all living organisms—could be the substance behind this mysterious mass. Their findings were published in PLOS Biology.
Polyphosphate: A New Hope?
Polyphosphate has been a part of life for billions of years and is believed to be involved in several neurodegenerative diseases. Previous experiments conducted by Jakob’s team demonstrated that polyphosphate stabilizes fibrils and reduces their toxic effects on cultured neurons. Furthermore, studies have shown that polyphosphate levels decrease with age in rat brains, which may be linked to the onset of neurodegenerative diseases.
However, while these findings were promising, scientists lacked direct evidence of polyphosphate’s role in the human brain. By constructing 3D models of human fibrils, Jakob’s team ran simulations that suggested polyphosphate perfectly aligns with the mystery density. The researchers also altered the fibril structure and found that when polyphosphate was absent, the fibrils no longer protected neurons from toxicity.
Although the team cannot definitively extract polyphosphate from patient-derived fibrils due to technical limitations, their evidence strongly supports the hypothesis that polyphosphate is the “mystery density.”
Looking Ahead:
Jakob and her colleagues propose that maintaining proper levels of polyphosphate in the brain may help slow the progression of neurodegenerative diseases. However, confirming this theory will require significant investment in time and resources. As Jakob notes, “We are still at a very early stage. It’s only very recently that it became clear that there are additional components in these fibrils.”
The researchers’ work adds an essential layer of understanding to the complex nature of fibrils and their potential role in disease. While the exact implications for treatment remain uncertain, this study marks an important step forward in the quest to better understand—and ultimately combat—Alzheimer’s, Parkinson’s, and other debilitating neurodegenerative diseases.
Reference:
“Amyloid accelerator polyphosphate fits as the mystery density in α-synuclein fibrils” by Philipp Huettemann, Pavithra Mahadevan, Justine Lempart, Eric Tse, Budheswar Dehury, Brian F. P. Edwards, Daniel R. Southworth, Bikash R. Sahoo, and Ursula Jakob, PLOS Biology, 31 October 2024. DOI: 10.1371/journal.pbio.3002650.
The study was supported by the National Institutes of Health and included collaborators from Howard Hughes Medical Institute, Manipal Academy of Higher Education, and the University of California, San Francisco.
