Parkinson’s Culprit Modeled
A computational model of alpha-synuclein as it aggregates
Under a microscope, the curious protein clumps that dot the brains of Parkinson’s patients stick out like the culprits they are. But no one has yet caught the protein—alpha-synuclein—in the act of causing disease. Now, investigators report in an April 2007 issue of FEBS Journal that they’re getting closer: they’ve modeled alpha-synuclein’s early aggregation and offered a detailed mechanism for its participation in neuron death.
“This is not just the first computational model of alpha-synuclein,” says Igor Tsigelny, PhD, an author of the paper and a computational biologist at the San Diego Supercomputer Center. “Up to now, there was no molecular concept of the aggregation going on.”
In the brain cells of Parkinson’s patients, alpha-synuclein first starts to cluster as a proto-fibril. It then forms fibril chains, and finally ends up in the dense clumps of fibrils called Lewy bodies. Some researchers have suggested in the past few years that alpha-synuclein knocks off neurons right at the begin- ning of aggregation, long before it can be detected as a Lewy body. Biochemical and structural evidence hints that when a few alpha-synuclein molecules first self-assemble into protfibrils, they can form pore-like ring structures. These may interact with the cell membrane and allow ions to enter the cell. The entrance of ions such as Ca2+ could lead to neuron death.
The computer model created by Tsigelny and his colleagues at the University of California, San Diego, supports this theory, providing detailed dynamics of alpha-synuclein hexamers and pentamers and their interaction with the cell membrane. What’s more, the model shows that another synuclein in the cell—beta-synuclein—blocks alpha-synuclein’s ring-making, suggesting at least one avenue for future inhibitory drug development.
Modeling such a complex aggregation wasn’t simple. Alpha-synuclein is a large protein (140 amino acids), and to model its hexamer interacting with the cell membrane required juggling around a million atoms, Tsigelny says.
Yet more than the size of alpha-synuclein, what made it difficult to model was its lack of structure. Alpha-synuclein is an intrinsically unstructured protein—one without a distinct three-dimensional shape. Most proteins consistently fold into a favored shape to do their jobs, a form that can be crystallized, imaged, and pored over. But unstructured proteins flop this way and that, even while performing their specific tasks, making them very difficult to pin down and study.
“We were not scared by an unstable protein,” Tsigelny states. And he and his coworkers developed an unusual “all-dynamic” approach to modeling the protein. None of the conformations are final—they are all considered intermediate and each may last only as long as half of a nanosecond. Nevertheless, Tsigelny says, even such fleeting intermediates may aggregate. The pore like aggregates, they found, are far more stable than single molecules of alpha-synuclein.
Having this model “is one step forward,” says Hilal Lashuel, PhD, professor at the Swiss Federal Institute of Technology in Lausanne, Switzerland. The UCSD model provides a structural basis for testing the hypothesis that alpha-synuclein forms toxic pores, he adds. But Lashuel also cautions that only biochemical and in vivo studies can prove whether alpha-synuclein pokes holes in neurons. “Isolating the toxic species is really the most difficult question we are dealing with. You have to catch it in the act.”