In neurodegenerative diseases like Alzheimer’s, the needle-like fibers that accumulate in the brain are not the real damage-doers. The culprits are intermediate protein structures, called small amyloid oligomers, made of a few proteins that misfold and aggregate. But the oligomer’s fleeting existence—sometimes lasting only minutes before forming the longer fibers—make them nearly impossible to study. HHMI investigator David Eisenberg has at last pinned down the structure of an amyloid oligomer.
“We wanted to find the toxic agent,” Eisenberg, at the University of California, Los Angeles, says about his research published March 9, 2012, in Science. “You can’t design drugs if you don’t know the structure of the toxic agent.”
Though the oligomers in major amyloid diseases such as Alzheimer’s, Parkinson’s, and even type 2 diabetes are short-lived, Eisenberg found one that lasts longer. The needle-like amyloid fibers in some cataracts take decades to form, so the oligomer state of these misfolded proteins can be easily trapped. Eisenberg and graduate student Arthur Laganowsky took advantage of these unhurried aggregates to study the cataract-forming protein, alpha-crystalline (ABC).
Lagonowsky used a computational algorithm to find the segments of the ABC protein responsible for forming the fibers. He then confirmed that the ABC oligomer had antibody affinities and toxicity patterns similar to those in the major amyloid diseases. Finally, using x-ray diffraction, Lagonowsky saw that the small oligomer consists of a cylinder of six protein chains. They dubbed the structure “cylindrin.”
“This cylinder looks sort of like those toys you get in Chinatown, where you put your fingers in and realize they’re stuck,” says Eisenberg. “It has a structure unlike any of the 70,000 structures catalogued in the open-source Protein Data Bank.”
Eisenberg hopes that understanding the cylindrin structure may lead to new approaches to studying the structures of the more elusive oligomers associated with major diseases. “The fundamentals are absolutely critical to understanding medicine,” he says. “Work in structure and computation of amyloid diseases is just starting.”