January, 2012 - Millions of individuals suffer in the United States and across the globe from Alzheimer’s disease (AD), a debilitating neurodegenerative disease that causes dementia. Researchers have been working from a variety of different angles to find ways to treat AD, but the foundation of treating or preventing AD can only be found in fully understanding AD disease progression. In 2011, in an international collaboration with Vincent Raussens, PhD, and Emilie Cerf, PhD, CHORI Associate Scientist Vasanthy Narayanswami, PhD, and coworkers made a paradigm-shifting discovery that has the potential to significantly help unravel the mystery of AD progression.
Dr. Raussens leads one of the most premier labs worldwide in the use of infared spectrometry to probe protein structures. This group utilized state-of-the-art attenuated total reflection-Fourier-transform infared (ATR-FTIR) spectroscopy to analyze two different structural states of the dense clustering, or aggregation, of amyloid proteins that are the physiological hallmark of AD.
"AD is a protein mis-folding disease," Dr. Narayanaswami says. "Proteins are long chains of peptides, and how the fold together is critically important for their proper function. In AD, mis-folded amyloid proteins aggregate outside the nerve cells, causing problems in the communication between the brain and the neurons."
The amyloid aggregates are primarily composed of amyloid beta-peptide, or Ab, but several different stages have been identified for Ab, with varying degrees of toxicity.
As Dr. Raussens explains, “Ab can exist as a single molecule, or as larger, soluble entities called oligomers, and eventually as insoluble fibrils. For decades, fibrils had been considered the major toxic form of Ab, as well as other mis-folded proteins, but during the last 10 to 15 years, research has shown that the oligomer state is actually the most toxic.”
Subsequently, much of the original research on amyloid states focused on the final fibril stage and its structure, which has been identified as being composed of parallel b-sheets, as if the protein chain was folded in pleats, like a curtain. Although it was assumed that the oligomer state was similarly composed of parallel b-sheets, no structural studies had confirmed it. The new study by Drs. Raussens, Cerf, Sarroukh and Narayanaswami, however, conclusively demonstrated for the first time that the oligomer structure was in fact, anti-parallel.
As a result, the paper was named the 2011 Paper of the Year for Structure, a subset of Biochemical Journal. The most cited publication of the year in their online Knowledge Environment, the study significantly contributed to increasing Structure's impact factor by two points.
|“Our study challenges the existing paradigm and shows that the oligomers are actually composed of anti-parallel Ab-sheets.”
The study is a game-changer in both AD research and the study of other neurodegenerative diseases that are similarly caused by protein mis-folding.
“This important finding has implications in different areas,” says Dr. Raussens. “To begin with, this peculiar structure explains how it would be physically possible for oligomers to interact with lipid membranes, which would allow the oligomer to be part of the toxic mechanism involved in AD. But in addition, it has a direct implication on the other mis-folded proteins involved in other diseases because it is assumed nowadays that most – if not all – of these proteins can form oligomers as well and that they share common structural features.”
“We are really proud of this award especially because it was completely unexpected for us,” Dr. Raussens says. “We are very grateful to all the people involved, but in particular to Biomedical Journal editorial office for showing interest in our, at that time, countercurrent results.”
While further research is needed to investigate how the amyloid changes from an anti-parallel oligomer to a parallel fibril, the landmark study has already changed the field of protein mis-folding research. In addition, the new understanding of oligomer structure provides new hope for eventually finding treatment or prevention strategies for all protein mis-folding diseases.
Thursday, May 17, 2012 12:50 PM