Scrapie-like prion protein accumulates in aggresomes of cyclosporin A-treated cells.

Prion diseases are infectious, sporadic and inherited fatal neurodegenerations that are propagated by an abnormal refolding of the cellular prion protein PrP(C). Which chaperones assist the normal folding of PrP(C) is unknown. The linkage of familial Gerstmann- Sträussler-Scheinker (GSS) syndrome with proline substitutions in PrP raised the prospect that peptidylprolyl cis-trans isomerases (PPIases) may play a role in normal PrP metabolism. Here we used cyclo sporin A (CsA), an immunosuppressant, to inhibit the cyclophilin family of PPIases in cultured cells. CsA-treated cells accumulated proteasome-resistant, 'prion-like' PrP species, which deposited in long-lived aggresomes. PrP aggresomes also formed with disease-linked proline mutants when proteasomes were inhibited. These results suggest mechanisms whereby abnormally folded cytosolic PrP may in some cases participate in the development of spontaneous and inherited prion diseases.