Structural changes within alpha-synuclein can make this protein more prone to clumping — a common feature of Parkinson’s — a research group found, a discovery that might lead to ways of stopping this disease in its early stages.
The study, “Extent of N-terminus exposure of monomeric alpha-synuclein determines its aggregation propensity,” was published in the journal Nature Communications.
A hallmark of Parkinson’s disease is the misfolding of the alpha-synuclein protein, which promotes its aggregation into clumps that are deadly to dopamine-producing nerve cells. These cells are responsible for releasing the neurotransmitter dopamine, which is critical for regulating brain cell activity and function.
Alpha-synuclein has a variety of conformational states that are constantly reconfiguring, depending on environmental cues. But exactly which conformations are prone to aggregation, and how mutations influence these different shapes is not known.
Researchers at the University of Cambridge set out to identify aggregation-prone conformations, and the environmental factors that destabilize non-aggregation prone conformations, leading them to favor clumping.
A better understanding, they suggest, could aid in developing therapies that stabilize the native alpha-synuclein in Parkinson’s and other diseases characterized by the buildup of toxic alpha-synuclein aggregates (synucleinopathies).
“We wanted to understand why the normally healthy, monomeric [single protein chains] and soluble aSyn [alpha-synuclein] suddenly starts to misfold,” Amberley Stephens, with the university’s Department of Chemical Engineering and Biotechnology and the study’s co-first author, said in a press release.
However, “this is made very difficult because aSyn has no true structure but exists as lots of intermediate structures or conformations that are highly dynamic,” Stephens said.
Researchers compared the initial conformation of a normal alpha-synuclein, one not prone to forming aggregates, to mutated forms of this protein that are more or less prone to clumping than is the normal protein. Mutations in the alpha-synuclein coding gene SNCA are often seen in familial cases of Parkinson’s.
Using tools developed at the University of Exeter, the proteins’ structure and dynamics were assessed in the presence of calcium, known to induce aggregation.
“Our collaborators at the University of Exeter have been working on instrument development, so that we are able to detect smaller and smaller differences between protein populations — this is particularly important for such a flexible protein like aSyn,” said Maria Zacharopoulou, the study’s other co-first author.
The N-terminus of alpha-synuclein, which is essentially the first part of the protein sequence, was found to be mostly responsible for the differences in susceptibility to aggregation. If this N-terminus had a conformation making it more exposed to its surroundings, the protein would open in the presence of calcium, turning it more prone to aggregation.
The more exposed this first part of the protein was, the faster it would also aggregate. In contrast, less exposed or “closed” structures were less prone to form clumps.
Overall, these findings shed light on early steps in the formation of toxic alpha-synuclein aggregates.
“We conclude that the perturbation of long-range interactions upon calcium binding to monomeric aSyn leads to an increase in N-terminus solvent exposure for some aSyn variants which correlates with their increased aggregation propensity,” the researchers wrote.
This work may aid in the discovery of treatment approaches that stabilize alpha-synuclein, preventing it from acquiring aggregation-prone configurations. Likewise, they might be able to convert clumping-prone protein structures into normal ones.
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