New Shape of Parkinson's Protein

Evidence reshaping the structure of a protein linked to Parkinson’s suggests a new mechanism for the formation of the disease’s characteristic protein aggregates.

By | August 14, 2011

Possible tetrameric structure of a-synuclein.IMAGE COURTESY OF HARVARD MEDICAL SCHOOL.

New findings, published this week in Nature, challenge the long-standing view that a-synuclein, a protein involved in Parkinson's disease, is a single, unfolded protein. Instead, the protein appears helical in shape, and is composed of four synuclein components. The results suggest an extra step in the process of protein clumping, in which the tetramer first falls apart into its individual protein parts before congealing into the fibrils seen in Parkinson's disease.

The results “really fit with what I was already thinking,” said Julia George, a professor at the University of Illinois, and who was not a researcher on this study. Other groups had previously found evidence that a-synuclein could take shape as a helical tetramer, but the new study is the first to suggest that the helical tetramer might be the most predominant form of the protein in cells. It “strengthens the idea that the helical conformation” is indeed the native form, she said.

The researchers blame the discrepancy between their findings and previous work on a-synuclein on detergents. “We realized that people had always used denaturing methods” to probe the structure of the protein, said Dennis Selkoe, the senior author of the paper and a professor at Brigham and Women's Hospital and Harvard Medical School. The process can break the bonds that knit together a protein's secondary or tertiary structure. “We thought we should try a non-denaturing method,” Selkoe said, but “we didn't know we'd come up with a completely different form.”

When he and his colleagues ran the protein on a non-denaturing gel, which did not include the detergents traditionally used to study the protein, the results suggested that the protein weighed approximately 56 kDafour times the weight of the 14 kDa a-synuclein monomer scientists had previously isolated.

Selkoe's team conducted several other assays to test whether the gel was telling the truth. Robert Edwards, a professor at the University of California, San Francisco, said the most convincing was analytical ultracentrifugation, which characterized the way the protein spun through a solution and confirmed the larger molecular weight.

Selkoe's group also found hallmark signals of a protein wound into a helical formation, suggesting the protein was not unfolded as previously believed.

Still, Edwards said, “it's not that this has completely wiped out our previous understanding” of a-synuclein as an unfolded monomer. It could simply be that both forms of the protein exist at some equilibrium in the cell, agreed Joseph Mazzulli, a research fellow at Massachusetts General Hospital, who was not involved in the research. “I don't know that it's the predominant species,” said Mazzulli, who added that he looks forward to follow up work resolving this question.

But just the realization that the tetramer form of the protein exists in the cell is valuable information towards finally understanding the role of a-synuclein. “The more we know about what synuclein is normally doing, the more we can understand how that is perturbed in Parkinson's disease,” George told The Scientist.

a-Synuclein occurs physiologically as a helically folded tetramer that resists aggregation,” T. Bartels, et al., Nature, doi:10.1038/nature10324, 2011.


Add a Comment

Avatar of: You



Sign In with your LabX Media Group Passport to leave a comment

Not a member? Register Now!

LabX Media Group Passport Logo

Popular Now

  1. How Gaining and Losing Weight Affects the Body
    Daily News How Gaining and Losing Weight Affects the Body

    Millions of measurements from 23 people who consumed extra calories every day for a month reveal changes in proteins, metabolites, and gut microbiota that accompany shifts in body mass.

  2. That Other CRISPR Patent Dispute
    Daily News That Other CRISPR Patent Dispute

    The Broad Institute and Rockefeller University disagree over which scientists should be named as inventors on certain patents involving the gene-editing technology.

  3. Neurons Use Virus-Like Proteins to Transmit Information
  4. EPO Revokes Broad’s CRISPR Patent
    The Nutshell EPO Revokes Broad’s CRISPR Patent

    Shortly after ruling out the earliest priority dates on a foundational patent for CRISPR gene-editing technology, the European Patent Office rescinded the patent entirely—and more are likely to follow.