An unlikely culprit in prion diseases

Forget the obvious. The toxicity of the prion protein (PrP) may have nothing to do with its most highly visible version: the infectious, detergent-resistant, plaque-forming fibrillar PrP^Sc seen in diseased brains of scrapie-infected sheep and mad cows. Instead, Jiyan Ma, Robert Wollmann (University of Chicago, Chicago, IL), and Susan Lindquist (MIT, Cambridge, MA) point the finger at cytosolic PrP.

Minor misfolding events probably lead to continual ejection of PrP from the ER into the cytosol for degradation by proteasomes. The team's inhibition of cytosolic proteasomes preferentially killed cells expressing PrP, and expression of PrP lacking ER translocation signals was highly toxic to neural cells both in vitro and in vivo. Transgenic mice producing cytosolic PrP suffered from unsteady gait and massive neuronal loss due to degeneration rather than problems in development. Thus, a cytosolic PrP rather than...