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Analytical Chemistry

High-resolution NMR structure of Parkinson’s disease fibril solved

Core of α-synuclein fibril has complex structure, including unusual Greek key topology

by Celia Henry Arnaud
April 1, 2016 | A version of this story appeared in Volume 94, Issue 14

The core of the α-synuclein fibril includes a tightly kinked Greek key.
Credit: Nat. Struct. Mol. Biol.

The hallmarks of many neurodegenerative diseases are brain proteins glomming together into amyloid fibrils. In Parkinson’s disease, for example, α-synuclein forms the fibril culprits.

So far, structural information on α-synuclein fibrils has been limited: Scientists have obtained high-resolution structures of parts of the fibrils, as well as low-resolution microscopy images of full-length ones.

Now, Chad M. Rienstra of the University of Illinois, Urbana-Champaign, and coworkers report the first structure of a full-length α-synuclein fibril with atomic resolution of the backbone. The structure they found is more complex than those of other protein aggregates associated with neurodegenerative diseases.

The team solved the α-synuclein structure on the basis of 68 spectra collected using 2-D and 3-D solid-state nuclear magnetic resolution spectroscopy (Nat. Struct. Mol. Biol. 2016, DOI: 10.1038/nsmb.3194). They used fibrils produced from cell cultures rather than ones collected from actual Parkinson’s patients.

Determining the structure was challenging. At about 14.5 kilodaltons, α-synuclein is much larger than other fibril-forming peptides and proteins. To determine the positions and distances of certain atoms relative to others in the fibril, the researchers made six samples with different isotope-labeling patterns. The patterns helped them figure out which cross-peaks in the 2-D and 3-D spectra were from intermolecular or intramolecular interactions.

About 50 residues in the protein are part of the highly structured fibril core. In addition to the expected β-sheets found in all amyloids, the structure contains a distinctive “Greek key” topology not seen in other fibrils. Other structural features such as steric zippers, a glutamine ladder, and an intermolecular salt bridge contribute to both the complexity and the stability of the fibril.

Ronald Melki of the Paris-Saclay Institute of Neuroscience, who studies protein misfolding and aggregation in neurodegenerative disease, notes that the structure differs from previously published models that were derived from shorter segments of α-synuclein. He thinks this means that α-synuclein can form fibrils with different structures. That’s because it is able to form a variety of intermediates that can “assemble into distinct fibrils with different properties.”

Rienstra’s team collaborated with Virginia M. Y. Lee’s group at the University of Pennsylvania to show that the fibrils they studied actually killed neurons in cell culture. “When we put the fibrils into neurons, endogenous α-synuclein is recruited and phosphorylated, which is consistent with the neurodegenerative cascade observed in Parkinson’s disease,” Rienstra says. The neurons died after a couple of weeks.

Next up for Rienstra’s group is learning whether fibrils that form in the brains of Parkinson’s patients have the same structure as the one they found. To do that, they’re collaborating with Paul Kotzbauer at Washington University Medical Center in St. Louis to look at fibrils from postmortem brain tissue of Parkinson’s patients. “We have some initial data that indicate that the structures of fibrils prepared from brain tissue are very similar to those in our in vitro samples.”

Rienstra hopes that the structures will eventually lead to methods for early diagnosis and treatment of Parkinson’s disease.


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