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    • 2018-05-09 12:05:10
    • Article ID: 694279

    SLAC's X-ray Laser Opens New View on Proteins Related to Alzheimer's Disease

    By placing the tiniest strands of proteins on one-atom-thick graphene, scientists capture promising X-ray laser images of these elusive biomolecules that play a key role in neurodegenerative diseases.

    • Credit: Greg Stewart/SLAC National Accelerator Laboratory

      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.

    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.

    LCLS is a DOE Office of Science user facility. Other researchers who contributed to this study came from the University of Zurich; Center for Cellular Imaging and Nano Analytics in Switzerland; DOE’s Lawrence Livermore National Laboratory; University of Canterbury; University of Gothenburg; University of Bordeaux; University of Copenhagen; ETH Zurich; University of Oxford; Diamond Light Source; and the University of Hamburg.

    This article is based in part on a DESY press release.

    Citation: Seuring, et alNature Communications, 9 May 2018 (10.1038/s41467-018-04116-9)


    SLAC is a multi-program laboratory exploring frontier questions in photon science, astrophysics, particle physics and accelerator research. Located in Menlo Park, Calif., SLAC is operated by Stanford University for the U.S. Department of Energy's Office of Science. For more information, please visit slac.stanford.edu.

    SLAC National Accelerator Laboratory is supported by the Office of Science of the U.S. Department of Energy. The Office of Science is the single largest supporter of basic research in the physical sciences in the United States, and is working to address some of the most pressing challenges of our time. For more information, please visit science.energy.gov.

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    Science Up-Close: Developing a Cookbook for Efficient Fusion Energy

    To develop a future fusion reactor, scientists need to understand how and why plasma in fusion experiments moves into a "high-confinement mode" where particles and heat can't escape. Scientists at the Department of Energy's Princeton Plasma Physics Laboratory simulated the transition into that mode starting from the most basic physics principles.

    Peering into the Mist: How Water Vapor Changes Metal at the Atomic Level

    New insights into molecular-level processes could help prevent corrosion and improve catalytic conversion.

    Neutron science publications reach new highs at ORNL's flagship facilities

    The High Flux Isotope Reactor and the Spallation Neutron Source at the Department of Energy's Oak Ridge National Laboratory have reached new levels of increased science productivity. In 2018, a record high of more than 500 scientific instrument publications were produced between HFIR and SNS--based on neutron beamline experiments conducted by more than 1,200 US and international researchers who used the world-leading facilities.

    Fiery sighting: A new physics of eruptions that damage fusion experiments

    Feature describes first direct sighting of a trigger for bursts of heat that can disrupt fusion reactions.

    Microbial Types May Prove Key to Gas Releases from Thawing Permafrost

    Scientists discover key types of microbes that degrade organic matter and release carbon dioxide and methane into the atmosphere.

    An effect that Einstein helped discover 100 years ago offers new insight into a puzzling magnetic phenomenon

    Experiments at the Department of Energy's SLAC National Accelerator Laboratory have seen for the first time what happens when magnetic materials are demagnetized at ultrafast speeds of millionths of a billionth of a second: The atoms on the surface of the material move, much like the iron bar did. The work, done at SLAC's Linac Coherent Light Source (LCLS) X-ray laser, was published in Nature earlier this month.

    Found: A precise method for determining how waves and particles affect fusion reactions

    Like surfers catching ocean waves, particles within plasma can ride waves oscillating through the plasma during fusion energy experiments. Now a team of physicists led by PPPL has devised a faster method to determine how much this interaction contributes to efficiency loss in tokamaks.

    Discovery adapts natural membrane to make hydrogen fuel from water

    In a recent study from the U.S. Department of Energy's (DOE) Argonne National Laboratory, scientists have combined two membrane-bound protein complexes to perform a complete conversion of water molecules to hydrogen and oxygen.

    How Plants Regulate Sugar Deposition in Cell Walls

    Identified genes involved in plant cell wall polysaccharide production and restructuring could aid in engineering bioenergy crops.

    Scientists Identify Gene Cluster in Budding Yeasts with Major Implications for Renewable Energy

    How yeast partition carbon into a metabolite may offer insights into boosting production for biofuels.


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    Top 10 Discoveries of 2018

    Every year, the U.S. Department of Energy's (DOE) Brookhaven National Laboratory compiles a list of the biggest advances made by the Lab's staff scientists, engineers, and visiting researchers. From uncovering mysteries of the universe to building better batteries, here, in no particular order, are our picks for the top 10 discoveries of 2018.

    U.S. Department of Energy Announces $33 Million for Small Business Research and Development Grants

    The U.S. Department of Energy announced it will award 189 grants totaling $33 million to 149 small businesses in 32 states.

    DOE to Provide $16 Million for New Research into Atmospheric and Terrestrial Processes

    The U.S. Department of Energy (DOE) announced a plan to provide $16 million for new observational research aimed at improving the accuracy of today's climate and earth system models.

    Machine learning award powers Argonne leadership in engine design

    When attempting to design engines to be more fuel-efficient and emissions-free, automotive manufacturers have to take into account all the complexity inherent in the combustion process.

    ORNL partners with industry to address multiple nuclear technology challenges

    The Department of Energy's Oak Ridge National Laboratory is collaborating with industry on six new projects focused on advancing commercial nuclear energy technologies that offer potential improvements to current nuclear reactors and move new reactor designs closer to deployment.

    Lithium earns honors for three physicists working to bring the energy that powers the sun to Earth

    Feature describes research of three PPPL physicists who have won the laboratory's 2018 outstanding research awards

    DOE approves technical plan and cost estimate to upgrade Argonne facility; Project will create X-rays that illuminate the atomic scale, in 3D

    The U.S. Department of Energy has approved the technical scope, cost estimate and plan of work for an upgrade of the Advanced Photon Source, a major storage-ring X-ray source at Argonne.

    Costas Soukoulis elected to National Academy of Inventors

    Costas Soukoulis, Ames Laboratory senior scientist and Iowa State University Frances M. Craig Endowed Chair and Distinguished Professor, has been named as a 2018 National Academy of Inventors (NAI) Fellow.

    Biophysicist F. William Studier Elected Fellow of the National Academy of Inventors

    F. William Studier, a Senior Biophysicist Emeritus at the U.S. Department of Energy's Brookhaven National Laboratory and Adjunct Professor of Biochemistry at Stony Brook University, has been elected as a Fellow of the National Academy of Inventors (NAI). He is among 148 renowned academic inventors being recognized by NAI for 2018.

    Blast to the future

    A grant from DOE's Technology Commercialization Fund will help researchers at Argonne and industry partners seek improvements to U.S. manufacturing by making discovery and design of new materials more efficient.


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    Rapid Lake Draining on Ice Sheets Changes How Water Moves in Unexpected Ways

    Widespread fracturing during lake drainage triggers vertical shafts to form that affect the Greenland Ice Sheet.

    New Historical Emissions Trends Estimated with the Community Emissions Data System

    The data system will allow for more detailed, consistent, and up-to-date global emissions trends that will aid in understanding aerosol effects.

    Peering into the Mist: How Water Vapor Changes Metal at the Atomic Level

    New insights into molecular-level processes could help prevent corrosion and improve catalytic conversion.

    Microbial Types May Prove Key to Gas Releases from Thawing Permafrost

    Scientists discover key types of microbes that degrade organic matter and release carbon dioxide and methane into the atmosphere.

    New Method Knocks Out Yeast Genes with Single-Point Precision

    Researchers can precisely study how different genes affect key properties in a yeast used industrially to produce fuel and chemicals.

    How Plants Regulate Sugar Deposition in Cell Walls

    Identified genes involved in plant cell wall polysaccharide production and restructuring could aid in engineering bioenergy crops.

    Scientists Identify Gene Cluster in Budding Yeasts with Major Implications for Renewable Energy

    How yeast partition carbon into a metabolite may offer insights into boosting production for biofuels.

    More Designer Peptides, More Possibilities

    A combined experimental and modeling approach contributes to understanding small proteins with potential use in industrial, therapeutic applications.

    Deep Learning for Electron Microscopy

    Artificial intelligence on Summit to discover atomic-scale structures.

    Clarifying Rates of Methylmercury Production

    New model provides more accurate estimates of how fast microbes produce a mercury-based neurotoxin.


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