Alpha-synuclein stepwise aggregation reveals features of an early onset mutation in Parkinson’s disease

Abstract

Amyloid formation is a process involving interconverting protein species and results in toxic oligomers and fibrils. Aggregated alpha-synuclein (αS) participates in neurodegenerative maladies, but a closer understanding of the early αS polymerization stages and polymorphism of heritable αS variants is sparse still. Here, we distinguished αS oligomer and protofibril interconversions in Thioflavin T polymerization reactions. The results support a hypothesis reconciling the nucleation-polymerization and nucleation-conversion-polymerization models to explain the dissimilar behaviors of wild-type and the A53T mutant. Cryo-electron microscopy with a direct detector shows the polymorphic nature of αS fibrils formed by heritable A30P, E46K, and A53T point mutations. By showing that A53T rapidly nucleates competent species, continuously elongates fibrils in the presence of increasing amounts of seeds, and overcomes wild-type surface requirements for growth, our findings place A53T with features that may explain the early onset of familial Parkinson’s disease cases bearing this mutation.

Guilherme de Oliveira and Jerson Silva combine cryo-electron microscopy and biochemical approaches to characterise the aggregation of alpa-synuclein into fibrils, a feature associated with Parkinson’s disease. They provide direct structural insights into the mechanism of polymerisation of a pathological A53T mutant.