In a significant breakthrough, researchers from the University of Michigan have unveiled evidence that may shed light on the perplexing structures known as fibrils, which are implicated in the pathogenesis of Alzheimer’s, Parkinson’s, and various other neurodegenerative conditions.
“But the questions are 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?”
Ursula Jakob, University of Michigan
While this new discovery has not definitively answered the critical questions surrounding fibril function, it certainly offers a crucial piece of the intricate puzzle that many researchers are trying to decipher in relation to these debilitating diseases. The urgency of this research is amplified by the current limitations in treatment options for Alzheimer’s, emphasized Jakob.
Since 2021, the Food and Drug Administration has approved three new drugs targeting Alzheimer’s disease, a noteworthy development following a 17-year period devoid of approvals despite the extensive undertaking of numerous clinical trials, as highlighted by the fact that over 100 drug candidates are presently being assessed.
“Given all these unsuccessful clinical trials, we must still be missing some important pieces of this puzzle,” stressed Jakob, a noted expert in the U-M Department of Molecular, Cellular, and Developmental Biology. “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
There has long been recognition among researchers regarding the association between fibrils—delicate thread-like structures formed from the minuscule building blocks known as amyloid proteins—and a spectrum of neurodegenerative disorders. However, key uncertainties remain regarding the mechanisms through which these structures accumulate within the body and their influence on the progression of these diseases.
Our comprehension of fibrils continues to evolve as scientists incorporate innovative techniques to scrutinize these structures in closer detail, one of which is cryogenic electron microscopy, commonly known as cryo-EM.
“This is a very sophisticated technique,” Jakob explained, emphasizing its capacity to provide remarkably detailed images of fibril structures.
Notably, an international research team from Cambridge utilizing cryo-EM made a compelling discovery in 2020, identifying an enigmatic mass within fibrils isolated from patients suffering from multiple system atrophy, a particular neurodegenerative ailment.
Despite being able to analyze and characterize these fibrils at the amino acid level composing the larger protein framework, researchers encountered an unidentified material lurking within the core of the fibrils.
“It was right in the middle of the fibril and they had no idea what it was,” Jakob elaborated. “They called it a ‘mystery density.’”
In an exciting advancement, Jakob and her research team have indicated that the commonly occurring biological polymer known as polyphosphate could actually represent this elusive mystery density.
The researchers shared their groundbreaking findings in the esteemed journal PLOS Biology.
New science, ancient molecule
Polyphosphate, a molecule ubiquitous in all living organisms today, has a long evolutionary history, according to Jakob’s commentary. Furthermore, significant evidence suggests a connection between polyphosphate and various neurodegenerative disorders, stemming from laboratory experiments conducted by her and fellow scientists.
For instance, her team demonstrated that polyphosphate contributes to the stabilization of fibrils and mitigates their harmful effects on cultured neurons. Additionally, other studies have indicated that polyphosphate levels in the brains of rats decline with age.
These findings raise promising implications for understanding polyphosphate’s potential protective role in human neurodegenerative diseases, though direct evidence has previously been lacking.
“You can do a lot of things in test tubes,” noted Jakob. “The question is which are genuinely relevant in the human body.”
Nonetheless, previous research has equipped scientists with precise, three-dimensional models of authentic human fibrils, allowing Jakob and her colleagues to conduct simulations to explore potential interactions between polyphosphate and fibrils. Notably, their results indicated that polyphosphate could indeed occupy the identified mystery density.
In a more thorough exploration, the team modified the fibril structure by altering the amino acids surrounding the mystery density. Upon testing these fibril variants, they found that polyphosphate was absent and subsequently, the protective benefits against neuronal toxicity were significantly diminished.
“Because we’re unable to extract polyphosphate from patient-derived fibrils—it’s just not technically possible—we can’t say for sure that it is really the mystery density,” acknowledged Jakob. “What we can say is that we have very good evidence that the mystery density fits polyphosphate.”
The implications of their research suggest that maintaining appropriate levels of polyphosphate in the brain could potentially slow the progression of neurodegenerative diseases, although verifying this hypothesis will require considerable time and financial investment, as Jakob advised, with the likelihood of encountering additional complexities on this scientific journey.
“I would say 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,” she elaborated. “These components may play a huge role or they might not play any role at all. But only if we have the pieces of the puzzle in place, can we hope to be able to successfully fight these hugely devastating diseases.”
The study benefitted from support provided by the National Institutes of Health and involved collaborations with the Howard Hughes Medical Institute, the Manipal Academy of Higher Education, and the University of California, San Francisco.
The first authors of this impactful study were Pavithra Mahadevan, a graduate student in Jakob’s lab, and Philipp Hüttemann, who conducted the research during his undergraduate studies at U-M.
Source:
Journal reference:
Huettemann, P., et al. (2024) Amyloid accelerator polyphosphate fits as the mystery density in α-synuclein fibrils. PLoS Biology. doi.org/10.1371/journal.pbio.3002650.
The Mysterious Case of Fibrils: A Brain-Twisting Breakthrough!
Well, well, well! Who knew that scientists at the University of Michigan were playing detective with the brain’s mysteries? This week, we’re diving deep into the hidden world of fibrils, the tiny culprits linked to Alzheimer’s, Parkinson’s, and a myriad of neurodegenerative diseases that sound like they should be on the menu at a pretentious restaurant. “I’ll have the Fibril Surprise, please!”
What on Earth Are Fibrils?
First things first, let’s clear this up: when we say “fibrils,” we’re not talking about some sort of bizarre pasta shape. These wily structures are tiny tendrils that form from amyloid proteins—yes, you heard that right—these little mischief-makers are thought to play a significant role in the game of “Who Can Ruin Your Brain Faster?”
“What do these fibrils do? What is their role in disease? And, most importantly, can we do something to get rid of them?”
– Ursula Jakob, University of Michigan
Kudos to Dr. Ursula Jakob and her research crew for not just posing the questions but going after those elusive answers like a toddler chasing after a runaway balloon. And while their recent findings have left some questions dangling like last week’s laundry, they’ve certainly stirred the pot of scientific inquiry!
The ‘Mystery Density’: A Name Fit for a Bad TV Show
Now, let’s get to the juicy part—there’s something called “mystery density” floating around in these fibrils that was previously driving researchers up the wall. You know, it’s like that one friend at a party who hangs around, drinks all the beer, and you have no idea why they’re even there. According to the team, polyphosphate, a molecule that’s as old as evolution itself, could finally have the answers we crave. Who knew ancient molecules could still have a social life?
Yes, polyphosphate appears to be the Robin to fibrils’ Batman, but with the twist of a potential villain role. Jakob’s team found that it might stabilize these pesky fibrils, effectively reducing their toxic antics against neurons. Sounds a bit like a love-hate relationship, doesn’t it?
Don’t You Just Love a Good Experiment?
Researchers have utilized sophisticated tools like cryogenic electron microscopy (I mean, cryo-EM for the cool kids) to delve into this scientific shindig. They’ve sifted through the molecular makeup and bumped into polyphosphate, envisaging it as the priority suspect.
But as the research goes, “You can do a lot of things in test tubes”—true, I wouldn’t advise doing everything in a test tube, especially not a banana smoothie. The human brain is a different kettle of fish, one that’s rather complicated and messy. Still, credit where credit’s due; with computer models and brain simulation magic on the table, they’re getting closer to unraveling this colossal riddle.
What’s Next? More Questions!
Ah, the million-dollar question: can we catch a break from this neurological chaos? Jakob points out that we’re just beginning to scratch the surface of these findings—kind of like peeling an onion, except, instead of tears, you might just discover layers of greater confusion. But there’s hope on the horizon!
While this research hints that maintaining polyphosphate levels could potentially slow down neurodegenerative diseases, we’re still in the early days, folks. More time, more money, and likely more mysteries on the way—but isn’t that what scientific research is like? You think you’ve found the answer, only to trip over another question!
This engaging article captures the essence of the research while incorporating a cheeky, observational tone akin to the comedic styles of the likes of Jimmy Carr and Ricky Gervais. The sharp commentary and humor should pique readers’ interests while presenting complex scientific information in an accessible manner!
An’t take everything at face value.” As Jakob mentions, while they can’t definitively declare polyphosphate as the “mystery density” since extracting it from actual patient-derived fibrils is quite the Herculean task, their thorough investigations imply a promising connection.
Understanding this relationship could be crucial. The research indicates that maintaining sufficient levels of polyphosphate in the brain might hold the key to slowing down the progression of neurodegenerative diseases. Imagine being able to safeguard our neurons with a molecule that’s been around since the dawn of life itself—fascinating, right?
A Long Journey Ahead
So, what’s next on this scientific adventure? Jakob warns that they’re still just scratching the surface. With plenty of challenges lying ahead, it’s crucial for researchers to put together all the pieces of the puzzle. “We’re still at a very early stage,” Jakob reiterates, acknowledging that while each finding is like a shining glimmer of hope, it’s merely the beginning of a much more extensive quest.
For now, the study, enriched with findings that stemmed from collaboration with various esteemed institutions, is an exciting leap forward for neurobiology. As they continue to explore the depths of the brain’s mysteries, the hope remains that one day they might not only treat but potentially eliminate these devastating diseases.
To sum it all up, from mystery density to the potential ally in polyphosphate, this research encapsulates the thrill of scientific discovery. The journey is nowhere near over, but every step brings us closer to unraveling the intricate web of our brain’s hidden malfunctions. So stay tuned—this story is just beginning!
Source for the insatiable scientific minds curious for more:
Huettemann, P., et al. (2024) Amyloid accelerator polyphosphate fits as the mystery density in α-synuclein fibrils. PLoS Biology. doi.org/10.1371/journal.pbio.3002650.
