‘A Decade of Discovery’ Hails Supercomputers Used in Parkinson’s Disease Breakthrough

A new book by the U.S. Department of Energy (DOE) commemorating the agency’s most significant scientific breakthroughs of the last decade includes the groundbreaking research by scientists at the San Diego Supercomputer Center to better understand the molecular mechanisms that cause Parkinson’s disease.

Called A Decade of Discovery, the new publication covers a wide array of transformational science and engineering research, divided into three broad categories: energy and the environment, national security, and life and physical science. The hardcover book highlights research done by the DOE’s 17 national laboratories, such as the development of new, cleaner and sustainable fuels; new anti-terrorism technologies to protect our troops and citizens; measures being taken to maintain a safe and reliable nuclear weapons stockpile; and better ways to detect and treat major diseases such as cancer, Parkinson’s, and other illnesses.

 

Start of penetration of alpha-synuclein to the membrane. Yellow is initial position; red is on the first stage of molecular dynamics simulations. Water molecules not shown. Source: Igor Tsigelny, San Diego Supercomputer Center, UC San Diego.

In the area of life and physical science, the DOE book highlights the work of a team led by Igor Tsigelny, a scientist at the San Diego Supercomputer Center (SDSC) and the Department of Chemistry and Biochemistry at the University of California, San Diego collaborating with the Argonne National Laboratory of the DOE.

Using supercomputer resources both at SDSC and Argonne, Tsigelny and his colleagues were able to elucidate for the first time the concrete molecular mechanism behind Parkinson’s disease, providing new insights into the illness and a promising avenue of treatment. The findings have also provided the tools for other researchers to aid in the study of other disorders associated with abnormally aggregated proteins, including Alzheimer’s and prion diseases.

While the tremors, rigid posture, and shuffling gait of Parkinson’s disease have been associated for decades with the die-off of dopamine-producing neurons in the brain, scientists did not know until recently how these neurons, riddled with suspicious protein clumps, are affected by the disease.

“We couldn’t have done this without the supercomputers,” Tsigelny is quoted as saying in the DOE book. “They gave us the power to track enough molecules over time to see the interactions we were looking for.”

Specifically, the protein clumps in Parkinson’s disease consist primarily of a protein called alpha synuclein (aS). For many years a prime target in Parkinson’s research, aS has resisted conventional protein analysis because it has an ever-changing shape.
 

Alpha-synuclein pentamer aggregate construction interrupted by beta-synuclein. Two possible low energy docking positions of beta-synuclein. (red and green). Source: Igor Tsigelny, San Diego Supercomputer Center, UC San Diego.

Tsigelny decided to study aS in motion using a computer modeling approach known as molecular dynamics. His new tool, called MAPAS (Membrane-Associated Protein Assessments), harnesses the power of supercomputers to study how this protein contacts cell membranes.

Tsigelny’s virtual view of pore formation enabled him to identify the protein-binding sites on aS proteins in a high level of detail. Further studies revealed that beta synuclein, a brain protein very similar to aS, appeared to inhibit aS molecules from linking together. Working with Eliezer Masliah, a professor of Neurosciences and Pathology at UC San Diego’s School of Medicine, Tsigelny and his team, which included Mark Miller and Yuriy Sharikov, used these findings to develop a compound capable of clogging interactions of aS molecules halting their aggregation and subsequent pore formation.

Tsigelny used his computer models to design and test the possible compounds that can prevent aggregation. Masliah’s later laboratory tests are very promising.  “If the studies would proceed in current direction it is quite possible that these will lead to the first drug to treat the cause of Parkinson’s disease instead of the symptoms,” according to Tsigelny. The treatment would offer hope to the more than 1 million people who are living with Parkinson’s disease today.