Prion infections come with strings attached

Misfolded prion proteins form extended amyloid strings on the surface of infected cells, Rouvinski et al. reveal.

The endogenous prion protein, PrP^C, is attached to lipid rafts on the plasma membrane by a C-terminal glycosylphosphatidylinositol (GPI) anchor. Infectious prion particles convert PrP^C to a misfolded conformation, PrP^Sc, that is subsequently trimmed down to a protease-resistant C-terminal fragment. PrP^Sc forms amyloid fibers when detergent-extracted from infected cells, but whether it aggregates on membranes in vivo and where it localizes in the cell are still uncertain, in part because antibodies to the protein’s C-terminal region fail to recognize PrP^Sc under physiological conditions.

Rouvinski et al. found, however, that antibodies against PrP^Sc’s N terminus could recognize the full-length prion in its native state in infected cells. Using these antibodies, the researchers discovered that PrP^Sc forms “strings,” up to 8 µm in length, on the surface of cells in culture and in the brains of infected mice. The strings fluoresced with thioflavin T, suggesting an amyloid structure, and contained both the full-length and cleaved forms of PrP^Sc, but they didn’t contain PrP^C at a detectable level. Live imaging revealed that the strings were largely immobile and remained on the cell surface for several hours. The slow rate of internalization might limit PrP^Sc’s degradation by lysosomal proteases and increase the prion’s ability to convert PrP^C to the misfolded conformation.

Senior author Albert Taraboulos now wants to investigate PrP^Sc string structure and determine how they affect the physiology of infected cells. The strings localize to enlarged lipid raft–like domains, which could have a major impact on cell signaling pathways.