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July 28, 2014

Simulations Link Common Brain Disorders

Tiffany Trader
cocaine_binding_site_Sahai

When a coalition of leading researchers from the US and the EU wanted to study brain disorders that involve disturbances of dopaminergic signaling, they turned to the powerful supercomputing resources of the Texas Advanced Computing Center.

Using the Extreme Science and Engineering Discovery Environment (XSEDE) cyberinfrastructure and TACC’s Stampede supercomputer, the research team uncovered a link between addiction and common neurological diseases including early-onset Parkinsonism and ADHD. The resulting study sheds light on the altered dopamine signaling that is present in each of these disorders.

Dopamine is a neurotransmitter that plays an important role in behavior, cognition and reward mechanisms. Disturbances in dopaminergic signaling are associated with brain diseases, including parkinsonism, attention deficit hyperactivity disorder (ADHD), autism, schizophrenia, and addiction, according to the team’s paper in the Journal of Clinical Investigation. Yet the pathophysiology of these diseases is still poorly understood.

One of the researchers on this team is Michelle Sahai, a postdoctoral associate at the Weill Cornell Medical College of Cornell University. “The present findings should provide a critical basis for further exploration of how dopamine dysfunction and altered dopamine transporter function contribute to brain disorders” said Sahai in a writeup on the TACC website. “It also contributes to research efforts developing new ways to help the millions of people suffering.”

Sahai is also interested in how addictive drugs like cocaine and amphetamie hijack the dopamine reward system. A protein called dopamine transporter usually works to reabsorb dopamaine back into the brain cell to put the breaks on the dopamine “feel good” reaction. But cocaine doesn’t allow this binding to take place, which allows dopamine levels to proliferate. This excess dopamine is associated with euphoria, increased energy and alertness.

Sahai is using Stampede to observe the binding of the dopamine transporter at the molecular level. The work requires very long simulations that would not likely be possible without leading-edge supercomputers, like Stampede.

Sahai is working along with other researchers to develop a drug that would bind to cocaine without suppressing the dopamine transporter. The computer simulations have also increased the understanding of diseases like Parkinson’s and other neurological disorders. Researchers from the University of Copenhagen, Copenhagen University Hospital, and other labs in the US and Europe have demonstrated the first known link between de novo mutations in the dopamine transporter and Parkinsonism in adults.

There is no cure for Parkinson’s yet, but this study lays the groundwork for more effective medications to help the seven to ten million people who are dealing with this diagnosis.

Science writer Makeda Easter has the full story on the TACC website.