Physiological and pathological functions of the prion protein homologue Dpl.

Abstract

A misfolded version of the prion protein PrP(C), known as PrP(Sc), is the major component of scrapie infectivity, the pathological agent in transmissible spongiform encephalopathies. The Prnp gene that encodes the cellular PrP(C) protein was cloned almost 20 years ago, but remained without sequence or structural relatives for over a decade. Only recently a novel protein, named Doppel (Dpl), was identified, which shares significant biochemical and structural homology with PrP(C). When overexpressed, Dpl is neurotoxic and causes a neurological disease. Strikingly, Dpl neurotoxicity is counteracted and prevented by PrP(C). In contrast to its homologue PrP(C), Dpl is dispensable for prion disease progression and for the generation of PrP(Sc), but Dpl appears to have an essential function in male spermatogenesis. Although Dpl research is still in its infancy, the discovery of Dpl has already solved some enigmas of prion biology and an understanding of its physiological function is emerging.