Prion protein complexed to RNA through the amino‐terminal domain aggregates and is toxic to neuroblastoma cells

Abstract

The conversion of the cellular prion protein (PrP), into its altered conformation – the PrPSc – is believed to be the major cause of prion diseases. Although PrP is until now the only identified agent of these diseases, there are several evidences that other molecules can modulate this conversion. We have identified that interaction of PrP with double-stranded DNA lead to a higher β-sheet content, with similar characteristics of PrPSc and have structurally characterized the PrP:DNA complex. RNA molecules can also interact with PrP and potentially modulate PrPC to PrPSc conversion or even bind differentially to both PrP isoforms. In this work we have investigated the interaction of recombinant full-length PrP and two PrP amino-terminal deletion mutants with distinct RNA sequences or total RNA extracted from cultured cells. We have shown that PrP interacts with RNA with nanomolar affinity and aggregates upon this interaction. RNA does not induce aggregation of the PrP N-terminal deletion mutants, indicating that the N-terminal region is important for this process. Cell viability assays showed that PrP:RNA aggregates are toxic to cultured cells. These results indicate that RNA can modulate recombinant prion protein conversion into toxic aggregates. Support: CNPq, FAPERJ, CAPES, IMBEBB, L’ÓREAL.