When the prion protein misfolds and aggregates in humans, it can cause fatal neurodegenerative diseases such as Creutzfeldt-Jakob disease and Gerstmann–Sträussler–Scheinker syndrome.
These diseases have different symptoms, partly because the prion protein can misfold into different shapes. Just how a single protein can misfold into different aggregate conformations, however, has confounded scientists.
Now, Motomasa Tanaka and colleagues at the RIKEN Brain Science Institute in Wako have reported that small clusters of prion proteins called oligomers, which develop from monomer proteins, determine the eventual shape of the larger prion aggregate1. The findings were published in the journal Nature Chemical Biology in collaboration with researchers from the United States and from the RIKEN SPring-8 Center in Harima.
The research team used a yeast model system to study prion misfolding and aggregation, because yeast contain a prion-like protein called Sup35. This yeast protein misfolds into different aggregate conformations that cause the yeast to turn various colors—from white to pink—when they are grown on nutrient plates. A synthetic version of Sup35 can also form these distinct conformations when grown at different temperatures.
Using various biophysical techniques, the researchers observed that the synthetic Sup35 formed oligomers when they were grown at a low temperature, but not at a high temperature. The Sup35 grown at a low temperature made the yeast turn white, while Sup35 grown at a high temperature made the yeast turn pink. This suggests that the oligomers, formed at only the low temperature, may be an intermediate step in the formation of the larger aggregates that cause the ‘white’ phenotype.
The team then investigated which amino acid region of Sup35 is involved in the formation of the oligomer. By mutating various amino acids of the Sup35 protein, the researchers found that the parts of the protein required for oligomer formation were different to those required for creation of the larger aggregate. In addition, while oligomer formation was involved in acquisition of the ‘white’ phenotype, it was not required for driving the growth of the larger prion aggregate. These findings suggest that oligomers serve as an initial scaffold to determine the eventual shape—and therefore the physiological characteristics—of the larger prion aggregate. Tanaka proposes that “inhibiting these interactions between prion proteins could become a therapeutic strategy for the neurodegenerative prion diseases.”
The corresponding author for this highlight is based at the Tanaka Research Unit, RIKEN Brain Science Institute
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