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Shape-shifting proteins play key role in Parkinson's disease

Alpha-synuclein embedded in the cell membrane. This position can lead to pore formation and subsequent cell death. Image courtesy Igor F. Tsigelny, SDSC.

Characterized by tremors and the progressive inability to control muscle movement, Parkinson's disease affects an estimated seven to 10 million people worldwide, and treatment costs can be quite steep.

Nobody knows for sure why Parkinson's disease occurs, but they do know how. It occurs when nerve cells in an area of the brain that controls movement become impaired or die. These nerve cells produce dopamine — an important brain chemical that acts as a messenger of sorts, telling different regions of the brain how to work together to produce smooth movements and other actions. When less dopamine is produced, messages don't go out like they should.

Nobody knows why the nerve cells are dying, but recent studies have determined that a protein called alpha-synuclein, formerly thought of as little more than cell garbage, turns out not to be quite so trashy. Alpha-synucleins bind to each other and create large shapes known as Lewy bodies, which are protein clumps found in the dying brain cells of those with some forms of Parkinson's disease and other neurological disorders. For many years, these clumps were considered the main reason for Parkinson's disease. However, recent studies have revealed that alpha-synuclein can also form ring-like structures in the cell membrane that lead to pore formation and eventual cell death.

Amino acids in alpha-synuclein proteins are sometimes replaced with other amino acids, which are then passed down through families. Some of the mutations drastically increase the probability of Parkinson’s disease in these families. Researchers have known about these mutations for more than 50 years, but have had little success in explaining their behavior until now.

"Nobody knew why this mutation was doing this," says Igor Tsigelny, a US research scientist with the San Diego Supercomputer Center (SDSC), as well as the University of California, San Diego Moores Cancer Center and Department of Neurosciences. "Why does it activate Parkinson's disease? If the answer could be found, it could be very useful for understanding the molecular mechanism of the disease and developing new drugs to treat it. Our goal was to find out the mechanism of this mutation's impact on the disease."

Sometimes referred to as a chameleon because it constantly changes shape, alpha-synuclein previously posed serious challenges for researchers. There were too many possible protein shapes to get a clear picture of what the proteins were doing, and to determine which shapes could lead to the disease.

A look under the hood at Gordon, the San Diego Supercomputer Center’s powerful supercomputer built specifically for the challenges of data-intensive computing. Image courtesy SDSC.

"We needed to study as many transformations and shapes of this protein as possible," says Tsigelny. "We needed to conduct hundreds of nanoseconds of molecular dynamics simulations to get the possible snapshots — millions of them."

These kinds of intense calculations would be impossible on a regular computer (and very possibly burn it out if one tried). Luckily, Tsigelny and his team have access to Gordon, SDSC's powerful supercomputer built specifically for the challenges of data-intensive computing. With large memory 'supernodes' and 300 terabytes of flash-based memory at its disposal, Gordon is uniquely positioned for problems like pinning down tricky alpha-synuclein long enough to figure out its role.

Thanks to the clearer picture Gordon presented, Tsigelny and his colleagues discerned that alpha-synuclein shapes are not random, as once thought. In fact, their shapes change in accordance with certain intrinsic rules. Computer modeling showed that alpha-synuclein can bind to the cell membrane at four main sites, or zones. Of the four, only one is significant. Alpha-synuclein molecules are particularly harmful when binding to the membrane by zone 2. They immediately and deeply penetrate the neuron membrane in this location. This leads to the creation of ring-like structures called ring oligomers, which open pores in the cell membrane and allow ions to pour in, ultimately killing the cell.

Knowing how the mutations in alpha-synuclein cause cell death is a first step in research to prevent the culprit from binding with the cell membrane — so ring oligomers never form. Researchers can now target the protein's interaction with zone 2 when developing new drugs in the fight against Parkinson's disease. 

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