In Nature researchers led by UCLA Professor David Eisenberg and Tamir Gonen (HHMI Janelia) offer closest look yet at core of α-synuclein aggregates.
The paper titled “Structure of the toxic core of α-synuclein from invisible crystals” was published in the September 9th online issue of the prestigious scientific journal. The research is receiving attention and accolades in the press:
Excerpt from ALZFORUM
Electron Microscope Yields Finer Structure of α-Synuclein, Aβ Fibrils
Protein aggregates associated with neurodegenerative disease have stubbornly resisted researchers’ efforts to get a good look at them. They refuse to crystallize well or yield to standard spectroscopic techniques. Now, advances in electron microscopy methods are forcing these molecules to give up their secrets. In the September 24 issue of Nature (published online on September 9), researchers led by David Eisenberg at the University of California, Los Angeles, and Tamir Gonen at the Howard Hughes Medical Institute’s Janelia Research Campus in Ashburn, Virginia, offer the closest look yet at the core of α-synuclein aggregates. The researchers made microscopic crystals from the peptides and used a relatively new technique called micro-electron diffraction to map them down to atomic resolution. Commenters called the work a tour de force. “[These] structures are the first to be determined by micro-electron diffraction from a molecule of previously unknown structure,” noted Yifan Cheng at the University of California, San Francisco, in an accompanying Nature commentary. Others were similarly impressed. “To obtain a structure of this quality from a peptide material with such tiny crystals is a remarkable feat, and will probably serve as the model for many other studies,” Gregory Petsko at Weill Cornell Medical College in New York told Alzforum. Tim Bartels at Brigham and Women’s Hospital, Boston, agreed, “The resolution here is unprecedented.” Image caption: β-Sheet Steric Zipper – Two views of the core portion of α-synuclein: looking down the fibril (top), and from the side (bottom). [Courtesy of Rodriguez et al., Nature.] Read full ALZFORUM article here.
Excerpt from C&EN News (by Stu Borman): Electron Diffraction Technique Reveals Structure Of Vanishingly Small Protein Crystals Structural Biology: MicroED yields new information about Parkinson’s aggregates To determine the high-resolution structure of some biomolecules, scientists use the well-established technique X-ray crystallography. But for that century-old method to work, they must first grow large crystals of the substances—one-tenth of a millimeter thick and larger, in most cases. Some biomolecules, however, are difficult to work with and form crystals that are too small to analyze this way. A report now shows that a technique called microED (microelectron diffraction) can determine the structures of biomolecules at atomic resolution by probing crystals with only about one-millionth the volume of those needed for X-ray crystallography. In the study, Tamir Gonen of Howard Hughes Medical Institute’s Janelia Research Campus; David S. Eisenberg of the University of California, Los Angeles; and coworkers used microED to determine the structures of aggregates of two peptides from α-synuclein that play key roles in Parkinson’s disease (Nature 2015, DOI: 10.1038/nature15368). The structures they obtained are similar to those uncovered by research teams studying amyloid-forming peptides involved in other neurodegenerative diseases, notes Michel Goedert of the Medical Research Council Laboratory of Molecular Biology (MRC LMB), in Cambridge, England, in a Nature commentary. But they also provide new information that could aid in the development of potential agents to fight Parkinson’s that inhibit α-synuclein aggregate formation. X-ray crystallography requires relatively large crystals because X-rays quickly damage small ones, destroying samples before they can be analyzed effectively. X-ray free-electron laser (XFEL) diffraction instruments use ultrafast pulses that can analyze crystals about one-thousandth the volume of those probed by conventional X-ray crystallography, but XFEL instruments are rare and expensive to use. Single-particle cryoelectron microscopy, which has become increasingly popular in recent years, doesn’t require crystals at all but is limited to analyzing only large biomolecules.
Image caption: Model depicts the structure of an aggregate formed by two peptides and a linking sequence from α-synuclein. MicroED determined structures of aggregates of the two peptides from tiny crystals. Credit: Courtesy of David Eisenberg and coworkers.