Physiological and pathological functions of the prion protein homologue Dpl

Abstract

A misfolded version of the prion protein PrPC, 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 PrPc 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 PrPC. When overexpressed, Dpl is neurotoxic and causes a neurological disease. Strikingly, Dpl neurotoxicity is counteracted and prevented by PrPC. In contrast to its homologue PrPC, Dpl is dispensable for prion disease progression and for the generation of PrPSc, 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.