It is widely believed that an altered version of the cell-surface glycoprotein PrP — known as PrPSc — has a pivotal role in transmissible prion diseases, such as the neurodegenerative disorder Creutzfeldt–Jakob disease. But, two papers by Lindquist and colleagues in Science Express now show that the true culprit for neurotoxicity is, in fact, not PrPSc.

PrP begins the journey from folding to the cell surface in the endoplasmic reticulum (ER). A substantial proportion of PrP misfolds, and this is detected by the quality-control mechanism, which transports the misfolded protein into the cytosol to be degraded by the proteasome.

In the first study, Ma and Lindquist showed that when proteasome activity is inhibited, cytosolic PrP accumulates and forms amorphous aggregates, and some of this converts to a PrPSc-like form.

So, which form is the killer? In the second study, Lindquist and colleagues found that it wasn't the conversion to PrPSc that led to neuron death, but rather the accumulation of PrP in the cytosol.

On the basis of their findings, Lindquist and colleagues have proposed a unifying model for PrP-associated diseases. A portion of PrP misfolds in the ER (this misfolding might be increased by disease-causing PrP mutations) and is retrogradely transported to the cytosol for proteasomal degradation. Normally, this misfolded PrP is degraded by the proteasome, but if the activity is compromised (for example, by stress or age), even small amounts of accumulated cytotoxic PrP can be neurotoxic. PrPSc is not the toxic species, but pathogenesis could be caused by PrPSc affecting the folding and transport of PrP.

The findings have both good and bad implications. First, alterations in PrP transport that prevent toxic accumulation of PrP in the cytosol could be a potential therapeutic strategy for prion diseases. Second, because interfering with normal proteasome function leads to the accumulation of cytosolic PrP, proteasome-inhibitor therapies (which are being developed for cancer) might need to be treated with caution.