Bridging the Distance Between Pathogenesis and Disease
CHORI Scientists Propose New Model for Protein Associated with Parkinson’s Disease
In a new study published in the September issue of Biochemistry – the official biochemical journal of the American Chemical Society – and highlighted as a “hot” article in their online press, CHORI scientists Vasanthy Narayanaswami, PhD, Shiori Tamamizu-Kato, PhD and their colleagues propose for the first time a model for the lipid membrane interaction of alpha-synuclein (alpha-syn), a soluble protein found primarily in neuronal tissues. Alpha-syn is most notable, however, for its potential role in the pathogenesis of Parkinson’s disease (PD).
“The Lewy bodies found in PD are composed predominantly of aggregated alpha-syn and lipids,” explains Dr. Narayanaswami. “It’s one of the hallmark features of the disease.”
Although it is generally well-accepted that the accumulation and aggregation of alpha-syn is a critical player in the development of PD, its structure and function have remained elusive to date.
“Normally, proteins have a primary and a secondary structure,” explains CHORI scientist Vasanthy Narayanaswami, PhD. “Imagine the primary structure as a chain of beads, with each bead being an amino acid.”
This strand of amino acid “beads” doesn’t remain linear, however, but folds into a secondary structure such as an alpha-helical or a beta-sheet structure.
“How a protein folds is an intrinsic property of that protein,” continues Dr. Narayanaswami. “But alpha-syn has no secondary structure and doesn’t fold in solution, which is very rare.”
The unstructured or linear state of alpha-syn has been known for some time. Alpha-syn, consists of an N terminal domain, a beta-amyloid binding domain, and a C terminal tail. What is not clear is how this unstructured form of the protein binds lipids, a critical step in ultimately identifying the process by which alpha-syn aggregates in the Lewy bodies associated with PD.
“What happens to alpha-syn when you present it with a membrane surface is that the N-terminal part of the protein forms an alpha-helical structure upon binding to the membrane,” Dr. Narayanaswami says. “The C-terminal tail, which is rich in negatively charged amino acid residues, does not bind because the cell membrane, which also has a negative charge, repels the tail.”
“What our model shows is that calcium, when added to alpha-syn after the N-terminal has bound with a lipid, serves as a bridge between the C-terminal tail and the membrane lipid, so that the whole protein, not just the N-terminal domain, is attached to the lipid surface.”
Even more interesting, is that when the C-terminal tail of alpha-syn binds with the lipids in the presence of calcium, it becomes a beta-sheet structure.
“Formation of a beta sheet structure is not very desirable in these kind of situations,” explains Dr. Narayanaswami, “because it represents an irreversible structure – it can not ever go back to the way it was. In fact, it becomes a template, with more proteins adding on to it creating a domino effect.”
As a result, the new calcium-triggered model of membrane interaction proposed by Dr. Narayanaswami, Dr. Tamamizu-Kato and their colleagues could describe the potential mechanisms responsible for the aggregation of alpha-syn in Lewy bodies. While their model provides a clue to the bridging mechanism in alpha-syn aggregation, it also represents a significant step toward bridging the gaps in our knowledge of the pathogenesis of PD.
This work was funded by grants from the Parkinson’s Disease Foundation and the Alzheimer’s Association.
Monday, May 16, 2011 11:33 PM