{"id":120705,"date":"2024-11-01T05:04:45","date_gmt":"2024-10-31T22:04:45","guid":{"rendered":"https:\/\/hotvideos24.online\/?p=120705"},"modified":"2024-11-01T05:04:45","modified_gmt":"2024-10-31T22:04:45","slug":"new-clues-on-protein-fibrils-could-transform-alzheimers-research","status":"publish","type":"post","link":"https:\/\/hotvideos24.online\/?p=120705","title":{"rendered":"New Clues on Protein Fibrils Could Transform Alzheimer\u2019s Research"},"content":{"rendered":"<p> <script async src=\"https:\/\/pagead2.googlesyndication.com\/pagead\/js\/adsbygoogle.js?client=ca-pub-3711241968723425\"\r\n     crossorigin=\"anonymous\"><\/script>\r\n<ins class=\"adsbygoogle\"\r\n     style=\"display:block\"\r\n     data-ad-format=\"fluid\"\r\n     data-ad-layout-key=\"-fb+5w+4e-db+86\"\r\n     data-ad-client=\"ca-pub-3711241968723425\"\r\n     data-ad-slot=\"7910942971\"><\/ins>\r\n<script>\r\n     (adsbygoogle = window.adsbygoogle || []).push({});\r\n<\/script><br \/>\n<\/p>\n<div>\n<p><strong>Summary: <\/strong>A recent study reveals that a polymer called polyphosphate may stabilize fibrils, protein structures linked to Alzheimer\u2019s, Parkinson\u2019s, and other neurodegenerative diseases. Researchers used computer models to show that polyphosphate fits a previously unidentified \u201cmystery density\u201d in these fibrils, suggesting it plays a protective role. While the findings could eventually inform therapies, more research is needed to understand polyphosphate\u2019s exact role in the brain.<\/p>\n<p>The discovery offers a crucial piece to the puzzle of neurodegenerative diseases, potentially leading to ways to slow disease progression. With polyphosphate implicated in fibril stability, scientists hope to harness this finding in developing future treatments. This study demonstrates the importance of molecular-scale insights in tackling complex brain diseases.<\/p>\n<p><strong>Key Facts:<\/strong><\/p>\n<ul class=\"wp-block-list\">\n<li>Polyphosphate may act as a stabilizing \u201cmystery density\u201d within fibrils linked to neurodegenerative diseases.<\/li>\n<li>Polyphosphate levels decline with age, which may affect the brain\u2019s resilience against protein aggregation.<\/li>\n<li>Computer models showed that polyphosphate aligns with fibrils, suggesting it could prevent their toxicity.<\/li>\n<\/ul>\n<p><strong>Source: <\/strong>University of Michigan<\/p>\n<p><strong>Research led by the University of Michigan has provided compelling\u00a0 evidence that could solve a fundamental mystery in the makeup of fibrils that play a role in Alzheimer\u2019s, Parkinson\u2019s and other neurodegenerative diseases.<\/strong><\/p>\n<p>\u201cWe\u2019ve seen that patients have these fibril structures in their brains for a long time now,\u201d said\u00a0Ursula Jakob, senior author of the new study. \u201cBut 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?\u201d<\/p>\n<figure class=\"wp-block-image size-full\"><picture fetchpriority=\"high\" decoding=\"async\" class=\"wp-image-105810\"><source type=\"image\/webp\" srcset=\"https:\/\/neurosciencenews.com\/files\/2024\/10\/alzheimers-fibrils-neurosicence.jpg.webp 1200w, https:\/\/neurosciencenews.com\/files\/2024\/10\/alzheimers-fibrils-neurosicence-300x200.jpg.webp 300w, https:\/\/neurosciencenews.com\/files\/2024\/10\/alzheimers-fibrils-neurosicence-770x513.jpg.webp 770w, https:\/\/neurosciencenews.com\/files\/2024\/10\/alzheimers-fibrils-neurosicence-1155x770.jpg.webp 1155w, https:\/\/neurosciencenews.com\/files\/2024\/10\/alzheimers-fibrils-neurosicence-370x247.jpg.webp 370w, https:\/\/neurosciencenews.com\/files\/2024\/10\/alzheimers-fibrils-neurosicence-293x195.jpg.webp 293w, https:\/\/neurosciencenews.com\/files\/2024\/10\/alzheimers-fibrils-neurosicence-150x100.jpg.webp 150w\" sizes=\"(max-width: 1200px) 100vw, 1200px\"\/><img fetchpriority=\"high\" decoding=\"async\" width=\"1200\" height=\"800\" src=\"https:\/\/neurosciencenews.com\/files\/2024\/10\/alzheimers-fibrils-neurosicence.jpg\" alt=\"This shows a brain.\" srcset=\"https:\/\/neurosciencenews.com\/files\/2024\/10\/alzheimers-fibrils-neurosicence.jpg 1200w, https:\/\/neurosciencenews.com\/files\/2024\/10\/alzheimers-fibrils-neurosicence-300x200.jpg 300w, https:\/\/neurosciencenews.com\/files\/2024\/10\/alzheimers-fibrils-neurosicence-770x513.jpg 770w, https:\/\/neurosciencenews.com\/files\/2024\/10\/alzheimers-fibrils-neurosicence-1155x770.jpg 1155w, https:\/\/neurosciencenews.com\/files\/2024\/10\/alzheimers-fibrils-neurosicence-370x247.jpg 370w, https:\/\/neurosciencenews.com\/files\/2024\/10\/alzheimers-fibrils-neurosicence-293x195.jpg 293w, https:\/\/neurosciencenews.com\/files\/2024\/10\/alzheimers-fibrils-neurosicence-150x100.jpg 150w\" sizes=\"(max-width: 1200px) 100vw, 1200px\"\/> <\/picture><figcaption class=\"wp-element-caption\">Now, Jakob and her colleagues have shown that a ubiquitous biological polymer called polyphosphate could be that mystery density. Credit: Neuroscience News<\/figcaption><\/figure>\n<p>Although the new finding does not explicitly answer those questions, it may provide a missing piece of the puzzle for researchers that are trying to understand how these diseases work at a molecular level. And it\u2019s clear that this more intimate understanding is needed, given the lack of Alzheimer\u2019s treatment options, Jakob said.<\/p>\n<p>The Food and Drug Administration has approved three new drugs for Alzheimer\u2019s disease since 2021, but that was preceded by a 17-year stretch without any new approvals despite hundreds of clinical trials (even now, there are more than 100 drug candidates being evaluated).\u00a0<\/p>\n<p>\u201cGiven all these unsuccessful clinical trials, we must still be missing some important pieces of this puzzle,\u201d said Jakob, a professor in the U-M Department of Molecular, Cellular, and Developmental Biology.<\/p>\n<p>\u201cSo 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.\u201d<\/p>\n<p><strong>The mystery density<\/strong><\/p>\n<p>Researchers have long known fibrils\u2014tiny tendrils assembled from invisibly small building blocks called amyloid proteins\u2014are connected to a number of neurodegenerative diseases. But important questions have lingered about how these structures build up in the body and how they affect the progression of these disorders.<\/p>\n<p>Our understanding of the fibrils continues to develop as scientists introduce new tools and methods to probe the structures more intimately. One of those innovations is known as cryogenic electron microscopy, or cryo-EM.<\/p>\n<p>\u201cThis is a very sophisticated technique,\u201d Jakob said. \u201cWith it you can see what these fibrils look like in great detail.\u201d<\/p>\n<p>In 2020, an international team led by researchers in Cambridge using cryo-EM discovered a mysterious mass inside fibrils that were recovered from patients with a neurodegenerative disease called multiple system atrophy.<\/p>\n<p>Although researchers could characterize the fibrils down to the individual amino acid units that build up the larger protein structure, there remained an unknown material running along the length of fibrils.<\/p>\n<p>\u201cIt was right in the middle of the fibril and they had no idea what it was,\u201d Jakob said. \u201cThey called it a \u2018mystery density.&#8217;\u201d<\/p>\n<p>Now, Jakob and her colleagues have shown that a ubiquitous biological polymer called polyphosphate could be that mystery density.\u00a0<\/p>\n<p>The team reported its findings in the journal\u00a0<em>PLOS Biology<\/em>.<\/p>\n<p><strong>New science, ancient molecule<\/strong><\/p>\n<p>Polyphosphate is a molecule found in every living thing today and has been used by organisms throughout the eons of evolution, Jakob said. It is also thought to have links to several neurodegenerative conditions thanks to laboratory experiments performed by Jakob and other scientists.<\/p>\n<p>For example, her team showed that polyphosphate helps stabilize fibrils and reduces their destructive potential against lab cultured neurons. Other researchers have shown that the amount of polyphosphate in rat brains decreases with age.<\/p>\n<p>These results imply polyphosphate could be important in protecting humans against neurodegenerative diseases. Still, scientists lacked direct evidence that it was.<\/p>\n<p>\u201cYou can do a lot of things in test tubes,\u201d Jakob said. \u201cThe question is which are genuinely relevant in the human body.\u201d<\/p>\n<p>The human brain, however, is an incredibly complex environment. Scientists have yet to design an experiment that can clearly elucidate polyposphate\u2019s role in it.\u00a0<\/p>\n<p>But scientists did have precise, 3D structures of real fibrils from humans thanks to earlier research. By creating computer models of those structures, Jakob and her team could run simulations that asked how polyphosphate would interact with a fibril. They found that it fit the mystery density very well.<\/p>\n<p>They then took it a step further and tweaked the structure of the fibril, changing the amino acids that bordered the mystery density. When they tested these fibril variants, they found that polyphosphate was no longer associated with them and no longer protected neurons against the fibrils\u2019 toxicity.<\/p>\n<p>\u201cBecause we\u2019re unable to extract polyphosphate from patient-derived fibrils\u2014it\u2019s just not technically possible\u2014we can\u2019t say for sure that it is really the mystery density,\u201d Jakob said.<\/p>\n<p>\u201cWhat we can say is that we have very good evidence that the mystery density fits polyphosphate.\u201d<\/p>\n<p>Their work leads to the hypothesis that finding a way to maintain proper polyphosphate levels in the brain could possibly slow the progress of neurodegenerative disease. But proving that will still take large investments of time and money, Jakob said, and there will likely be new mysteries to be solved along the way.<\/p>\n<p>\u201cI would say we are still at a very early stage. It\u2019s only very recently that it became clear that there are additional components in these fibrils,\u201d she said.<\/p>\n<p>\u201cThese 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.\u201d<\/p>\n<p>The work was supported by the National Institutes of Health and included collaborators from Howard Hughes Medical Institute, the Manipal Academy of Higher Education and the University of California, San Francisco.<\/p>\n<p>The first authors of the study were\u00a0Pavithra Mahadevan, a graduate student in Jakob\u2019s lab, and Philipp H\u00fcttemann, who performed the research as an undergraduate at U-M.\u00a0<\/p>\n<h2 class=\"wp-block-heading\">About this neurology research news<\/h2>\n<p class=\"has-background\" style=\"background-color:#ffffe8\"><strong>Author:<\/strong> <a href=\"http:\/\/neurosciencenews.com\/cdn-cgi\/l\/email-protection#e78a86939397889593a7928a8e848fc9828392\" target=\"_blank\" rel=\"noreferrer noopener\">Matt Davenport<\/a><br \/><strong>Source: <\/strong><a href=\"https:\/\/umich.edu\" target=\"_blank\" rel=\"noreferrer noopener\">University of Michigan<\/a><br \/><strong>Contact: <\/strong>Matt Davenport \u2013 University of Michigan<br \/><strong>Image: <\/strong>The image is credited to Neuroscience News<\/p>\n<p class=\"has-background\" style=\"background-color:#ffffe8\"><strong>Original Research: <\/strong>Open access.<br \/>\u201c<a href=\"https:\/\/journals.plos.org\/plosbiology\/article?id=10.1371\/journal.pbio.3002650\" target=\"_blank\" rel=\"noreferrer noopener\">Amyloid Accelerator Polyphosphate Implicated as the Mystery Density in \u03b1-Synuclein Fibrils<\/a>\u201d by Ursula Jakob et al. <em>PLOS Biology<\/em><\/p>\n<hr class=\"wp-block-separator has-text-color has-pale-cyan-blue-color has-alpha-channel-opacity has-pale-cyan-blue-background-color has-background\"\/>\n<p><strong>Abstract<\/strong><\/p>\n<p><strong>Amyloid Accelerator Polyphosphate Implicated as the Mystery Density in \u03b1-Synuclein Fibrils<\/strong><\/p>\n<p>Aberrant aggregation of \u03b1-Synuclein is the pathological hallmark of a set of neurodegenerative diseases termed synucleinopathies.<\/p>\n<p>Recent advances in cryo-electron microscopy have led to the structural determination of the first synucleinopathy-derived \u03b1-Synuclein fibrils, which contain a non-proteinaceous, \u201cmystery density\u201d at the core of the protofilaments, hypothesized to be highly negatively charged.<\/p>\n<p>Guided by previous studies that demonstrated that polyphosphate (polyP), a universally conserved polyanion, significantly accelerates \u03b1-Synuclein fibril formation, we conducted blind docking and molecular dynamics simulation experiments to model the polyP binding site in \u03b1-Synuclein fibrils.<\/p>\n<p>Here, we demonstrate that our models uniformly place polyP into the lysine-rich pocket, which coordinates the mystery density in patient-derived fibrils.<\/p>\n<p>Subsequent in vitro studies and experiments in cells revealed that substitution of the 2 critical lysine residues K43 and K45 with alanine residues leads to a loss of all previously reported effects of polyP binding on \u03b1-Synuclein, including stimulation of fibril formation, change in filament conformation and stability as well as alleviation of cytotoxicity.<\/p>\n<p>In summary, our study demonstrates that polyP fits the unknown electron density present in in vivo \u03b1-Synuclein fibrils and suggests that polyP exerts its functions by neutralizing charge repulsion between neighboring lysine residues.<\/p>\n<p> <!-- Form created by Optin Forms plugin by WPKube: create beautiful optin forms with ease! --> <!-- https:\/\/wpkube.com\/ --><!--optinforms-form5-container--> <!-- \/ Optin Forms --> <\/div>\n<p><script async src=\"https:\/\/pagead2.googlesyndication.com\/pagead\/js\/adsbygoogle.js?client=ca-pub-3711241968723425\"\r\n     crossorigin=\"anonymous\"><\/script>\r\n<ins class=\"adsbygoogle\"\r\n     style=\"display:block\"\r\n     data-ad-format=\"fluid\"\r\n     data-ad-layout-key=\"-fb+5w+4e-db+86\"\r\n     data-ad-client=\"ca-pub-3711241968723425\"\r\n     data-ad-slot=\"7910942971\"><\/ins>\r\n<script>\r\n     (adsbygoogle = window.adsbygoogle || []).push({});\r\n<\/script><br \/>\n<br \/><div data-type=\"_mgwidget\" data-widget-id=\"1660802\">\r\n<\/div>\r\n<script>(function(w,q){w[q]=w[q]||[];w[q].push([\"_mgc.load\"])})(window,\"_mgq\");\r\n<\/script>\r\n<br \/>\n<br \/><a href=\"https:\/\/neurosciencenews.com\/polyphosphate-alzheimers-fibrils-27957\/\">Source link <\/a><\/p>\n","protected":false},"excerpt":{"rendered":"<p>Summary: A recent study reveals that a polymer called polyphosphate may stabilize fibrils, protein structures linked to Alzheimer\u2019s, Parkinson\u2019s, and other neurodegenerative diseases. 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