Researchers at North Carolina State University have figured out how copper induces misfolding in the protein associated with Parkinson disease, leading to creation of the fibrillar plaques which characterize the disease. This finding has implications for both the study of Parkinson disease progression, as well as for future treatments.
The protein in question, alpha-synuclein, is the major component of fibrillar plaques found in Parkinson patients. Researchers had already discovered that certain metals, including copper, could increase the rate of misfolding by binding with the protein, but were unsure of the mechanism by which this binding took place.
"We knew that the copper was interacting with a certain section of the protein, but we didn't have a model for what was happening on the atomic level," says Frisco Rose PhD candidate in physics and lead author of the paper describing the research.
Rose and NC State colleagues Dr Miroslav Hodak, research assistant professor of physics, and Dr Jerzy Bernholc, Drexel Professor of Physics and Director of the Center for High Performance Simulation, developed a series of computer simulations designed to ferret out the most likely binding scenario.
According to Hodak, "We simulated the interactions of hundreds of thousands of atoms, which required multiple hundred thousand CPU-hour runs to study the onset of misfolding and the dynamics of the partially misfolded structures."
The number of calculations was so large that Hodak and Bernholc had to devise a new method to make it possible for a computer to process them. Only supercomputers like Jaguar, Oak Ridge National Laboratory's most powerful supercomputer – the most powerful in the United States, in fact – were up to the task. But the simulations finally revealed the binding configuration most likely to result in misfolding.
Their results appear in the June 14 edition of Nature Scientific Reports.
The researchers hope that their finding will advance our understanding of Parkinson disease. "Understanding the molecular mechanism of Parkinson's disease should help researchers in developing drugs that treat the disease rather than merely alleviate symptoms," Bernholc says.
The research was funded by the Department of Energy and the National Science Foundation. The Department of Physics is part of NC State's College of Physical and Mathematical Sciences.
Source: News Release
North Carolina State University
June 14, 2011