Science + Technology

Alzheimer’s, Parkinson’s, Type II Diabetes Are Similar at the Molecular Level, UCLA and International Scientists Report

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Alzheimer's disease, Parkinson's disease, type IIdiabetes, the human version of mad cow disease and other degenerative diseasesare more closely related at the molecular level than many scientists realized,an international team of chemists and molecular biologists reported April 29 inthe online version of the journal Nature (print version to follow).

Harmful rope-like structures known as amyloid fibrils, which are linked protein molecules that form inthe brains of patients with these diseases, contain a stack of water-tight"molecular zippers," the scientists report.

"We have shown that the fibrils have a commonatomic-level structure," said David Eisenberg, director of the UCLA–Departmentof Energy Institute of Genomics and Proteomics, a Howard Hughes MedicalInstitute investigator and a member of the research team. "All of thesediseases are similar at the molecular level; all of them have a dry steric zipper. With each disease, a different proteintransforms into amyloid fibrils, but the proteins arevery similar at the atomic level."

The research, while still preliminary,could help scientists develop tools for diagnosing these diseases and,potentially, for treating them through "structure-based drug design,"said Eisenberg, a UCLA professor of chemistryand molecular biology.

The researchers, including scientistswith the European Synchrotron Radiation Facility in Grenoble, France, report11 new three-dimensional atomic protein structures, including those for both ofthe main proteins that form amyloid fibrils inAlzheimer's disease.

"Ithas been a joy to see so many new structures," said Michael Sawaya,a research scientist with UCLA and the Howard Hughes Medical Institute and amember of the team. "Each one is like a Christmas present. Now that we have somany of these that we can classify, I am thrilled to see each three-dimensionalarrangement of atoms, what the structural similarities and differences are, andwhich of the differences are significant. We see many similarities, but thereare details that are different. As we study more structures, we expect todetermine the common features among them.

"Itis clear from the positions of the atoms where the zipper is," Sawaya added. "Like pieces in a jigsaw puzzle, they have tofit together just right. We are finding out how they fit together. We don't yetknow all the ways of forming the zippers; we are working to fill in the missingpieces and are hopeful of doing so. Thanks to our colleagues in Grenoble and Copenhagen,technology is not limiting us."

Inan earlier Nature paper (June 9, 2005), Eisenberg and his colleagues reportedthe three-dimensional structure of an amyloid-likeprotein from yeast that revealed thesurprising molecular zipper.

"In 2005, we were like prospectors who found flakesof gold in a stream," Eisenberg said. "Now we see the real nuggets. In thispaper, we present atomic-level structures for crystals related to fibrils fromproteins associated with numerous human diseases."

The research shows that very shortsegments of proteins are involved in forming amyloidfibrils; Eisenberg and his colleagues know some of the segments. Knowing thesegments makes it easier to design tests to detect whether a new drug iseffective, Eisenberg noted. Several proteins contain more than one amyloidfibril-forming segment.

"It's exciting how rapidly this work is progressing," said RebeccaNelson, a UCLA senior postdoctoral fellow with the UCLA-DOE Institute ofGenomics and Proteomics and a member of the team. "Once we formed the collaborationwith the scientists in Franceto use the European Synchrotron Radiation Facility, everything became easier."

Nelsondescribes the proteins associated with Alzheimer's and other amyloid fibril diseases as "transformer" proteins thatinstead of doing their normal work start forming pathological fibrilstructures.

Eisenberg's research team used asophisticated computer algorithm to analyze proteins known to be associatedwith human diseases. Magdalena Ivanova, a senior researchscientist, found that when the computer algorithmsays a protein will form an amyloid fibril, theprotein almost always does.

Whilethe molecular zipper is very similar in all cases, there are differences, whichare cataloged in this Nature paper. For example, while the amyloidfibrils are all characterized by a "cross-beta X-ray diffraction pattern" in asmall section of the protein that the scientists call the spine, and there arealways two sheets, the sheets can be face to face, or face to back.

Ifthe molecular zipper is universal in amyloid fibrils, as Eisenberg believes, is it possible topry open the zipper or prevent its formation?

MelindaBalbirnie, a UCLA postdoctoral scholar and a memberof the research team, is able to produce fibrils and has developed a test,using a wide variety of chemical compounds, to determine whether the fibrilsbreak up. She is "hopeful" her strategy will succeed in breaking up thefibrils.

Amystery on which the new Nature paper sheds light is what causes differentstrains of prions (infectious proteins) in which theprotein sequence is identical.

"Ourresearch gives a strong hypothesis that the origin of prionstrains is encoded in the packing of the molecules in the fibrils which we areseeing in the crystals," Ivanova said.

Theresearch unfolded over nearly a decade. A key breakthrough occurred when theUCLA team began working closely with Christian Riekel,a distinguished scientist at the European SynchrotronRadiation Facility in Grenoble, France, who studies the crystal structures ofsmall-scale molecules with an X-ray microcrystallographyinstrument, and Anders Madsen, Riekel's formergraduate student, who is now with the Universityof Copenhagen in Denmark. Riekelinvented ways to get a fine beam of X-rays to bombard microcrystals.He and Madsen were able to collect valuable diffraction data.

"Ithas been a great international collaboration," Eisenberg said.

Co-authors onthe research, in addition to Riekel and Madsen, are Shilpa Sambashivan, a recentgraduate student in Eisenberg's laboratory who is now a postdoctoral fellow atStanford University; UCLA graduate students Stuart Sievers,Marcin Apostol, Jed Wiltzius and Heather McFarlane, all members of Eisenberg'slaboratory; and Michael J. Thompson, a former postdoctoral scientist in thelaboratory;

"We could not have done this long-termresearch without substantial funding and are very grateful to the Howard HughesMedical Institute, the National Institutes of Health and the National ScienceFoundation for supporting our research," Eisenberg said.

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