Scientists at UCSB have used a new spectroscopic method to observe the assembly of amyloid fibrils — long-chain proteins that form in patients with certain diseases, such as Alzheimer’s disease and diabetes.
The paper, published in the journal Nature Chemistry, details the use of ion-mobility spectrometry-mass spectrometry, or IMS-MS, to observe the difference between how amyloid proteins self-assemble in model systems of amyloid diseases. The study was done by a research group led by UCSB chemistry professor Michael T. Bowers, who is the lead author of the study.
Christian Bleiholder, the first author of the study and a Humboldt postdoctoral fellow at UCSB, said the spectroscopic method they used to study the amyloid fibril formation has been developed very recently.
“The method we used is a combination of mass spectrometry and ion-mobility spectroscopy,” Bleiholder said. “Our method is new; there are no commercial devices available for performing it.”
In healthy patients, the amyloid peptide assembly results in randomly assembled, globular protein oligomers, while patients with certain diseases have the peptides assemble into fibrillar beta-sheet structures. While the fibrils themselves are not explicitly toxic, Bleiholder said the intermediate steps between the starting pieces of the fibril and the complete fibril may be the toxic agents that cause a variety of maladies, ranging from Alzheimer’s disease to atherosclerosis.
“The problem with these diseases is that in order to make a drug, you need to know the structure of the toxic agent. Currently, we do not have a target; we do not know what polymer causes this disease. So we need a method to tell us what the target is, and we did not have that before.”
Bleiholder said the researchers were the first to observe the self-assembly process directly, while previous methods had left the intermediate stages of the amyloid formation mysterious and not well-known.
What the scientists observed when they tracked the amyloid formation in the disease model was a conformational transition — a change in molecular shape — that led to the beta-sheet formation of fibrils. This was seen early in the assembly process. On the other hand, the control models showed no conformational transitions.
According to Bleiholder, the study opens new doors into the study of how amyloid fibers form, possibly leading to advances in the diagnosis, treatment and prevention of amyloid diseases.
“What is the most important aspect of this study is that we now have a method to observe this [assembly],” Bleiholder said.
Bleiholder said he will continue to study the fibril intermediates to determine which ones may be toxic agents.
The researchers seek to use IMS-MS to help discover more information that may lead to advances in the treatment and prevention of Alzheimer’s disease, Type 2 diabetes, Huntington’s disease, Parkinson’s disease, atherosclerosis and other amyloid diseases.
Thomas Wyttenbach, a UCSB associate researcher, was a co-author of the study along with former Ph.D. student Nicholas Dupis, who now resides at the University of Colorado as a postdoctoral fellow.