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  • richardmitnick 4:41 pm on May 10, 2018 Permalink | Reply
    Tags: Alzheimer’s and Parkinson’s, , ,   

    From SLAC Labs: “SLAC’s X-ray Laser Opens New View on Proteins Related to Alzheimer’s Disease” 


    From SLAC Labs

    May 9, 2018
    Angela Anderson

    1
    Experiments at SLAC’s Linac Coherent Light Source show the promise of using X-ray free-electron lasers to better understand the structure and function of amyloid fibrils, tiny protein strands that play a role in diseases like Alzheimer’s and Parkinson’s. In this illustration, X-ray light penetrates a sample of amyloid fibrils placed on the honeycomb-like carbon lattice of graphene, a new method that produces cleaner data because the thin graphene virtually disappears from view. (Greg Stewart/SLAC)

    SLAC/LCLS

    To learn more about diseases such as Alzheimer’s and Parkinson’s, scientists have zeroed in on invisibly small protein filaments that bunch up to form fibrous clusters called amyloids in the brain: How do these fibrils form and how do they lead to disease?

    Until now, the best tools for studying them have generated limited views, largely because the fibrils strands are so complex and tiny, just a few nanometers thick.

    Now an international research team has come up with a new method with potential for revealing the structure of individual amyloid fibrils with powerful beams of X-ray laser light. They describe it in a report published today in Nature Communications.

    In experiments conducted at the Linac Coherent Light Source (LCLS) at the Department of Energy’s SLAC National Accelerator Laboratory, the scientists placed up to 50 fibrils at a time on a layer of graphene, whose carbon atoms are arranged in a honeycomb-like pattern, and hit them with bursts of X-ray laser light. The graphene, it turned out, was almost transparent to the X-rays, and this allowed them to probe the structures of the delicate fibrils without picking up significant extraneous signals from the graphene layer in individual snapshots.

    While the team did not uncover the complete fibril structure, they said the innovative method they developed at LCLS opens up a promising path for amyloid studies using X-ray free-electron lasers, or XFELs, such as LCLS.

    Carolin Seuring, a scientist at the Center for Free-Electron Laser Science (CFEL) at DESY in Germany and principal author of the paper, said the results suggest this technique could even be used to determine the structure of individual fibrils.

    “There is a common consensus that it is not the amyloid fiber alone, but rather the protofilaments composing the fiber and the process of fibril formation that are toxic to the cell,” she said. “XFEL-based experiments have the potential to overcome the challenges we’ve faced in better understanding amyloid fibrils.”

    The Problem with Amyloids

    While amyloid fibrils are believed to play a major role in the development of neurodegenerative diseases, scientists have recently discovered that they also have other functions, Seuring said.

    “The ‘feel-good hormone’ endorphin, for example, can form amyloid fibrils in the pituitary gland,” she said. “They dissolve into individual molecules when the acidity of their surroundings changes, after which these molecules can fullfil their purpose in the body. Other amyloid proteins, such as those found in post-mortem brains of patients suffering from Alzheimer’s, accumulate as amyloid fibrils in the brain, and cannot be broken down and therefore impair brain function in the long term.”

    Accurate information about the structure of amyloid fibrils can inform scientists about their function, she added.

    “Our aim is to understand the role of the formation and structure of amyloid fibrils in the body and in the development of neurodegenerative diseases,” Seuring said.

    One barrier to studying amyloid fibrils is that they cannot be grown as crystals, which are the conventional targets for structural studies using X-rays. And because individual amyloid fibrils are so small, they don’t produce a measurable signal when exposed to X-rays. Scientists typically line up millions of fibrils parallel to each other to amplify the signal, but information about their individual differences is lost in the process.

    “A major part of our understanding about amyloid fibrils is derived from nuclear magnetic resonance and cryo-electron microscopy data,” Seuring said. But these methods are also of limited value for seeing individual differences between amyloid fibrils or observing their formation. “The structural analysis of amyloids is complex and examining them using existing methods is hampered by differences between the fibrils within a single sample,’” she said “Being able to look at the individual components of the sample would make it possible to determine the 3D structure of one type of fibril at a time.”

    The New Approach

    Earlier attempts to study fibrils at X-ray lasers delivered them into the path of the beam in jets of fluid. Switching to a solid graphene carrier gave the team two advantages, according to CFEL’s Henry Chapman, a professor at the University of Hamburg and a lead scientist at DESY.

    Because graphene is just one layer of atoms thick, it leaves hardly a trace in the diffraction patterns formed by X-rays scattering off the fibrils, which are used to determine their structures, he said. And the regular structure of the graphene encourages the fibrils to all line up in the same direction.

    This allows diffraction patterns to be obtained from fewer than 50 amyloid fibrils. Based on the results, the team hopes to eventually get patterns from single fibrils. To get to that goal, new methods of exposing a single fibril to the XFEL beam will need to be developed, according to Seuring: “With enough snapshots, a full 3D data set of a single fibril should be possible.”

    The exceptionally bright and narrowly focused beam at LCLS’s Coherent X-ray Imaging instrument was also key to the team’s success in taking data from such a small number of fibrils, according to SLAC staff scientist Mengning Liang.

    Intense X-ray pulses at XFELs limit the exposure of delicate samples to damaging X-rays. In this study, the fibrils were exposed for only a few femtoseconds, or millionths of a billionth of a second. Before the molecules are destroyed, information about their structure can be read by detectors.

    “Fibrils are a third category of samples that can be studied with the ‘diffract before destroy’ method at XFELs, in addition to single particles and crystals,” Liang said. “In some regards, fibrils fit between the other two: they have regular, recurring variations in structure like crystals, but without the rigid crystal structure.”

    The scientists tested their method on samples of well-studied tobacco mosaic virus filaments and smaller amyloid fibrils, some of which are associated with certain types of cancer. The tests produced structural data with a high degree of accuracy: The resolution in the diffraction images was almost on the scale of a single atom.

    “It is amazing that we are essentially carrying out the same experiments as Rosalind Franklin did on DNA in 1952, which led to the discovery of the double helix, but now we are reaching the level of single molecules,” says Chapman.

    See the full article here .

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    SLAC is a multi-program laboratory exploring frontier questions in photon science, astrophysics, particle physics and accelerator research. Located in Menlo Park, California, SLAC is operated by Stanford University for the DOE’s Office of Science.

     
  • richardmitnick 10:07 am on February 14, 2017 Permalink | Reply
    Tags: Alzheimer’s and Parkinson’s, ,   

    From Rutgers: “Alzheimer’s May Be Linked to Defective Brain Cells Spreading Disease” 

    Rutgers University
    Rutgers University

    February 13, 2017
    Robin Lally

    Rutgers study finds toxic proteins doing harm to neighboring neurons.

    1
    Rutgers scientists have discovered that toxic proteins may be spreading neurodegeneration and diseases like Alzheimer’s and Parkinson’s. No image credit.

    Rutgers scientists say neurodegenerative diseases like Alzheimer’s and Parkinson’s may be linked to defective brain cells disposing toxic proteins that make neighboring cells sick.

    In a study published in Nature, Monica Driscoll, distinguished professor of molecular biology and biochemistry, School of Arts and Sciences, and her team, found that while healthy neurons should be able to sort out and rid brain cells of toxic proteins and damaged cell structures without causing problems, laboratory findings indicate that it does not always occur.

    These findings, Driscoll said, could have major implications for neurological disease in humans and could possibly be the way that disease can spread in the brain.

    “Normally the process of throwing out this trash would be a good thing,” said Driscoll. “But we think with neurodegenerative diseases like Alzheimer’s and Parkinson’s there might be a mismanagement of this very important process that is supposed to protect neurons but, instead, is doing harm to neighbor cells.”

    Driscoll said scientists have understood how the process of eliminating toxic cellular substances works internally within the cell, comparing it to a garbage disposal getting rid of waste, but they did not know how cells released the garbage externally.

    “What we found out could be compared to a person collecting trash and putting it outside for garbage day,” said Driscoll. “They actively select and sort the trash from the good stuff, but if it’s not picked up, the garbage can cause real problems.”

    Working with the transparent roundworm, known as the C. elegans, which are similar in molecular form, function and genetics to those of humans, Driscoll and her team discovered that the worms – which have a lifespan of about three weeks — had an external garbage removal mechanism and were disposing these toxic proteins outside the cell as well.

    Ilija Melentijevic, a graduate student in Driscoll’s laboratory and the lead author of the study, realized what was occurring when he observed a small cloud-like, bright blob forming outside of the cell in some of the worms. Over two years, he counted and monitored their production and degradation in single still images until finally he caught one in mid-formation.

    “They were very dynamic,” said Melentijevic, an undergraduate student at the time who spent three nights in the lab taking photos of the process viewed through a microscope every 15 minutes. “You couldn’t see them often, and when they did occur, they were gone the next day.”

    Research using roundworms has provided scientists with important information on aging, which would be difficult to conduct in people and other organisms that have long life spans.

    In the newly published study, the Rutgers team found that roundworms engineered to produce human disease proteins associated with Huntington’s disease and Alzheimer’s, threw out more trash consisting of these neurodegenerative toxic materials. While neighboring cells degraded some of the material, more distant cells scavenged other portions of the diseased proteins.

    “These findings are significant,” said Driscoll. “The work in the little worm may open the door to much needed new approaches to addressing neurodegeneration and diseases like Alzheimer’s and Parkinson’s.”

    See the full article here .

    Follow Rutgers Research here .

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    Rutgers, The State University of New Jersey, is a leading national research university and the state’s preeminent, comprehensive public institution of higher education. Rutgers is dedicated to teaching that meets the highest standards of excellence; to conducting research that breaks new ground; and to providing services, solutions, and clinical care that help individuals and the local, national, and global communities where they live.

    Founded in 1766, Rutgers teaches across the full educational spectrum: preschool to precollege; undergraduate to graduate; postdoctoral fellowships to residencies; and continuing education for professional and personal advancement.

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