Two papers published in EMBO Journal hint at a neuroprotective function for the cellular prion protein, PrPC. Mutations in this protein, or changes in conformation induced by the infective prion protein PrPSc, can cause spongiform encephalopathies such as scrapie, bovine spongiform encephalopathy and Creutzfeldt–Jakob disease.

However, the function of PrPC is still a mystery. It is not even clear whether the neurodegeneration that is associated with spongiform encephalopathies is caused by a loss of the normal function of PrPC or by a gain of toxic function by PrPSc. The apparent absence of a phenotype in prion-knockout mice argued for the latter, but evidence is accumulating that cellular prions might have a neuroprotective role, the loss of which could cause cell death in prion diseases.

The two new papers both come from the same research group. One, by Zanata et al., shows that the cellular prion binds to a heat-shock-related protein, stress-inducible protein 1 (STI1), and that the interaction between these two proteins at the cell surface can rescue cultured retinal cells from apoptosis induced by treatment with anisomycin. A functional role for this interaction is supported by the finding of both proteins on neuronal cell surfaces in the central nervous system. The second paper, by Chiarini et al., shows that binding of PrPC by a peptide that recognizes the STI1-binding site (known as PrR) also protects neurons against apoptosis in vitro. It goes further to demonstrate that this protection depends on an increase in the levels of cyclic AMP that activates protein kinase A.

Many questions are outstanding. For example, it is unclear how the binding of PrPC at the outer membrane activates adenylyl cyclase, which is normally regulated by G proteins on the inner membrane. And it remains to be shown that the neuroprotective effect of PrPC–STI1 binding is physiologically relevant in vivo, or that it is disrupted by infection with PrPSc. But a fuller understanding of signalling and neuroprotection by PrPC should help us to understand the pathogenesis of prion disorders as well as the underlying cell biology of these proteins.