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The DOE Science News Source is a Newswise initiative to promote research news from the Office of Science of the DOE to the public and news media.
  • 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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No Longer Whistling in the Dark: Scientists Uncover a Little-Understood Source of Waves Generated Throughout the Universe

Scientists at the U.S. Department of Energy's Princeton Plasma Physics Laboratory (PPPL) and other laboratories, using data from a NASA four-satellite mission that is studying reconnection, have developed a method for identifying the source of waves that help satellites determine their location in space.

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Nucleation a boon to sustainable nanomanufacturing

Young-Shin Jun, professor of energy, environmental & chemical engineering in the School of Engineering & Applied Science, and Quingun Li, a former doctoral student in her lab, are the first to measure the activation energy and kinetic factors of calcium carbonate's nucleation, both key to predicting and controlling the process.

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Argonne scientists and their collaborators have developed a new model that merges basic electrochemical theory with theories used in different contexts, such as the study of photoelectrochemistry and semiconductor physics, to describe phenomena that occur in any electrode.


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Department of Energy Announces $218 Million for Quantum Information Science

The U.S. Department of Energy (DOE) announced $218 million in funding for 85 research awards in the important emerging field of Quantum Information Science (QIS).

Energy Secretary awards researchers for global threat reduction

Seven employees from the U.S. Department of Energy's (DOE) Argonne National Laboratory were among those presented with a Secretary of Energy Achievement Award at the Secretary's Honors Awards ceremony in Washington, D.C., on August 29.

University of Minnesota to lead $5.3 million federal grant to improve electronic circuit design

The University of Minnesota announced today that it has received a four-year, $5.3 million grant from the Defense Advanced Research Projects Agency (DARPA), an agency of the U.S. Department of Defense, to lead an effort that could spark the next wave of U.S. semiconductor innovation and broaden the competitive field for circuit design.

Berkeley Lab to Build an Advanced Quantum Computing Testbed

Lawrence Berkeley National Laboratory (Berkeley Lab) will receive $30 million over five years from the U.S. Department of Energy to build and operate an Advanced Quantum Testbed (AQT) allowing researchers to explore superconducting quantum processors to advance scientific research

Cheng wins Midwest Energy News' 40 Under 40 Award

Lei Cheng, an assistant chemist in the Materials Science division at the U.S. Department of Energy's (DOE) Argonne National Laboratory, has received a Midwest Energy News 40 Under 40 Award.

JCESR renewed for another five years

The U.S. Department of Energy (DOE) today announced its decision to renew the Joint Center for Energy Storage Research (JCESR), a DOE Energy Innovation Hub led by Argonne National Laboratory and focused on advancing battery science and technology.

Binghamton designated as NextFlex New York Node for flexible hybrid electronics initiative

NextFlex has designated Binghamton University to be the New York "Node" for its flexible hybrid electronics (FHE) initiative. As the NextFlex New York Node, Binghamton will design, develop and manufacture tools; process materials and products for flexible hybrid electronics; and attract, train and employ an advanced manufacturing workforce, building on the region's existing electronics manufacturing base.

First Particle Tracks Seen in Prototype for International Neutrino Experiment

The largest liquid-argon neutrino detector in the world has just recorded its first particle tracks, signaling the start of a new chapter in the story of the international Deep Underground Neutrino Experiment (DUNE). DUNE's scientific mission is dedicated to unlocking the mysteries of neutrinos, the most abundant (and most mysterious) matter particles in the universe.

Tais Gorkhover Wins LCLS Young Investigator Award for Pioneering Novel X-ray Imaging Methods

Tais Gorkhover, a principal investigator with the Stanford PULSE Institute, will receive the 2018 LCLS Young Investigator Award, granted to early-career scientists in recognition of exceptional research using the Linac Coherent Light Source (LCLS) X-ray free-electron laser at the Department of Energy's SLAC National Accelerator Laboratory.

ORNL, United Kingdom Lab Partner on Nuclear Energy Research

The United Kingdom's National Nuclear Laboratory and the U.S. Department of Energy's Oak Ridge National Laboratory have agreed to cooperate on a wide range of nuclear energy research and development efforts that leverage both organizations' unique expertise and capabilities.


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Breaking the Symmetry Between Fundamental Forces

Scientists improve our understanding of the relationship between fundamental forces by re-creating the earliest moments of the universe.

Water Plays Unexpected Role in Forming Minerals

Water molecules line up tiny particles to attach and form minerals; understanding how this happens impacts energy extraction and storage along with waste disposal.

Heavy Particles Get Caught Up in the Flow

First direct measurement show how heavy particles containing a charm quark get caught up in the flow of early universe particle soup.

Seeing Between the Atoms

New detector enables electron microscope imaging at record-breaking resolution.

Scaling Up Single-Crystal Graphene

New method can make films of atomically thin carbon that are over a foot long.

Discovered: Optimal Magnetic Fields Suppress Instabilities in Tokamak Plasmas

U.S. and Korean scientists show how to find and use beneficial 3-D field perturbations to stabilize dangerous edge-localized modes in plasma.

New Electron Glasses Sharpen Our View of Atomic-Scale Features

A new approach to atom probe tomography promises more precise and accurate measurements vital to semiconductors used in computers, lasers, detectors, and more.

Getting an Up-Close, 3-D View of Gold Nanostars

Scientists can now measure 3-D structures of tiny particles with properties that hold promise for advanced sensors and diagnostics.

Small, Short-Lived Drops of Early Universe Matter

Particle flow patterns suggest even small-scale collisions create drops of early universe quark-gluon plasma.

Tuning Terahertz Beams with Nanoparticles

Scientists uncover a way to control terahertz radiation using tiny engineered particles in a magnetic field, potentially opening the doors for better medical and environmental sensors.


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