Prefibrillar aggregates of yeast prion Sup35NM and its variant are toxic to mammalian cells.

The deposition of proteins as insoluble amyloid aggregates is a characteristic feature of more than 20 degenerative conditions. A growing body of evidence indicates that the oligomeric species formed by proteins, but not the mature fibrils, are inherently toxic and are associated with clinical diseases. The N-terminal and middle region of Sup35 (Sup35NM), a yeast prion, can assemble into oligomers and fibrils. Here we analyze the cytotoxicity of different aggregates of Sup35NM and its variant, the proteins that is not associated with clinical disease. Our results showed that prefibrillar aggregates generated from Sup35NM and its variant Sup35NM-1 were toxic to cultured mammalian cells. In addition, the activation of caspase-3, 8, and 9 were detected, suggesting that apoptosis was involved in the observed cytotoxicity. Our findings provide evidence for the underlying mechanism of amyloid aggregate-induced cytotoxicity and suggest that it may arise from common structural features of the aggregates rather than from primary amino acid sequences.