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Parkinson's disease

When protein clusters misbehave

CORNELL (US) — New research offers stunning visual evidence of a wide array of protein clusters with varying molecular structures—some of which might be key to understanding Parkinson’s disease.

The findings, published in the Nov. 2 edition of Proceedings of the National Academy of Sciences (PNAS), offer new clues into what happens when the protein alpha-synuclein, which is associated with Parkinson’s disease, undergoes abnormal aggregation.

Parkinson’s disease patients have dense lesions in their midbrains called Lewy bodies, which involve aggregates of alpha-synuclein. But it is still unclear whether Lewy bodies are a symptom of the disease or are themselves responsible for cell death.

Many researchers surmise that smaller clusters (known as oligomers or aggregates) of alpha-synuclein protein could be responsible for initiating neurodegeneration.

A team at Cornell University has been investigating structural changes in alpha-synuclein. Using chemical solutions of fluorinated alcohol to trigger protein structural transitions, the researchers observed the formation of irregular, helical aggregates that may be similar to formations in the brain of Parkinson’s disease patients.

These structures, some long and thin, and others inter-wound or spooled, could suggest alternative pathways to alpha-synuclein aggregation in the brain.

“These ringlike annular aggregates have been seen with atomic force microscopy before, and people have been interested in them for a long time,” says Valerie Anderson, first author and a graduate student. The research shows that the aggregates maybe involved in infiltrating healthy cells and causing disease, which could result in toxicity.

The researchers were able to identify early events in the assembly of these structures. By examining the interaction of types of polarized light with the alpha-synuclein protein, they observed rearrangements of the protein on the molecular level prior to aggregation.

Additional changes in the molecular conformation occurred when the proteins stuck together; alpha-synuclein adopts a helical structure that converts to an aligned, sheetlike molecular assembly early in the aggregation process.

These latest results shed light on early events that occur when alpha-synuclein behaves badly, although more research must be done to determine whether similar events take place in the brains of Parkinson’s disease patients.

The work was supported by the National Science Foundation and National Institutes of Health.

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