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August 22, 2011
Volume 89, Number 34
p. 7

Disease Protein’s Mistaken Identity

Biochemistry: Biologists thought α-synuclein was an unfolded monomer, but new research reveals a tetramer

Celia Henry Arnaud

Harvard Medical School
Dennis Selkoe describes his group's discovery that the natural form of α-synuclein, the protein that aggregates in the Lewy bodies associated with Parkinson's disease, is a helically folded tetramer, not an unfolded monomer as people thought.
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A new study upends a major aspect of what biologists thought they knew about the Parkinson’s protein α-synuclein. For more than 15 years, they have believed that the normal form of α-synuclein in cells is an unfolded monomer. Instead, the protein is a helically folded tetramer, report Dennis J. Selkoe and coworkers at Harvard Medical School (Nature, DOI: 10.1038/nature10324).

Aggregates of α-synuclein are a hallmark of Parkinson’s disease, and mutations in the protein cause rare familial forms of the disease. A better understanding of α-synuclein’s structure could help biologists figure out its normal function and provide a new therapeutic target for Parkinson’s disease.

Most researchers study bacterially expressed recombinant forms of α-synuclein, which scientists can readily produce in large quantities. But Selkoe, Tim Bartels, and Joanna G. Choi extracted and purified the protein directly from mammalian cells. Then, instead of examining the size of the purified protein in gels containing dyes and detergents, both of which can denature the protein, they used clear native gels. In the gel, the protein’s migration indicated that it was about four times the expected size of a monomer.

Analytical ultracentrifugation likewise confirmed that the protein is a tetramer. Circular dichroism spectra revealed the tetramer’s helical character.

This graphic shows what an α-synuclein tetramer might look like. Wikimedia Commons/Jawahar Swaminathan and MSD Staff at the European Bioinformatics Institute
This graphic shows what an α-synuclein tetramer might look like.

“We weren’t looking for a completely new insight,” Selkoe says. “Tim just did his analyses in a nondenaturing, nonharsh way. When he did, we saw this tetramer.”

Another group, led by Gregory A. Petsko, Dagmar Ringe, and Thomas C. Pochapsky at Brandeis University, has seen similar tetramers in recombinant α-synuclein from bacteria. Petsko says he has long been uncomfortable with the idea that the normal form of synuclein is unstructured. “About 1% of the protein in the central nervous system is α-synuclein,” he says. “Do you really believe that 1% of the protein in a neuron is going to look like a plate of spaghetti?”

So he and his coworkers went looking for a structured form of α-synuclein. “We found if we treated the protein carefully and gently it came out as a tetramer,” he says. With NMR, they found that the tetramer is helical but dynamic, so pinning down a precise structure is difficult. Their work has not yet been published.

The tetramers resist aggregation, according to the Harvard work. The Harvard researchers speculate that before the protein can aggregate, the tetramers must first break apart into monomers. And therein lies a potential therapeutic strategy. “We would like to screen small molecules,” Selkoe says, “to see if any of them can stabilize the tetramer against disassembly.”

“If the hypothesis that α-synuclein adopts a defined quaternary structure stands the test of time, then this structural insight represents a new paradigm for developing tetramer-stabilizing strategies to prevent α-synuclein aggregation linked to Parkinson’s disease,’’ says Jeffery W. Kelly, professor of chemistry at Scripps Research Institute.

Selkoe and Petsko collaborate on other research related to Alzheimer’s disease. While chatting about another project, they discovered that they had both seen these unusual synuclein structures. “It really helped that both of us had seen something like this,” Petsko says. “This was so contrary to orthodoxy that you’d be reluctant to publish it or talk about it if you were the only person who’d seen it.”

Selkoe (left) and Bartels found that α-synuclein is normally a tetramer. Harvard Medical School
Selkoe (left) and Bartels found that α-synuclein is normally a tetramer.
Chemical & Engineering News
ISSN 0009-2347
Copyright © 2011 American Chemical Society
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