Chemists have identified the complex chemical structure of the protein that stacks together to form fibrils in the brains of Parkinson's disease patients. In Parkinson's, the protein alpha-synuclein forms long fibrils that disrupt brain activity. This is similar to the beta-amyloid fibrils that form in Alzheimer's disease patients. However, while the beta-amyloid structure is known, the alpha-synuclein structure has eluded researchers as a result of its complexity, its insolubility and the difficulty of characterizing one protein within a fibril.
The group used a special type of molecular imaging called magic-angle spinning nuclear magnetic resonance to measure the placement of atoms in six different samples of alpha-synuclein. In each set of samples, they looked at different sets of atoms, then used advanced computational power to put them all together like pieces of a giant jigsaw puzzle.
Over 200 unique long-range distance restraints define a consensus structure with common amyloid features including parallel, in-register β-sheets and hydrophobic-core residues, and with substantial complexity arising from diverse structural features including an intermolecular salt bridge, a glutamine ladder, close backbone interactions involving small residues, and several steric zippers stabilizing a new orthogonal Greek-key topology. These characteristics contribute to the robust propagation of this fibril form, as supported by the structural similarity of early-onset-PD mutants.
The group experimentally verified the structure with collaborators by producing the protein in the lab and checking it with various imaging methods to see if it matched the fibrils found in Parkinson's patients. They also verified it biologically by testing it in cell cultures and seeing that it indeed behaved like the protein found in patients.
Structure of Parkinson's protein unraveled!
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