Normal neurogenesis and scrapie pathogenesis in neural grafts lacking the prion protein homologue Doppel

The agent that causes prion diseases is thought to be identical to PrPSc, a conformer of the normal prion protein PrPC. Recently a novel protein, term ed Doppel (Dpl), was identified that shares significant biochemical and str uctural homology with PrPC. To investigate the function of Dpl in neurogene sis and in prion pathology, we generated embryonic stem (ES) cells harbouri ng a homozygous disruption of the Prnd gene that encodes Dpl. After in vitr o differentiation and grafting into adult brains of PrPC-deficient Prnp(0/0 ) mice, Dpl-deficient ES cell-derived grafts contained all neural lineages analyzed, including neurons and astrocytes. When Prnd-deficient neural tiss ue was inoculated with scrapie prions, typical features of prion pathology including spongiosis, gliosis and PrPSc accumulation, were observed. Theref ore, Dpl is unlikely to exert a cell-autonomous function during neural diff erentiation and, in contrast to its homologue PrPC, is dispensable for prio n disease progression and for generation of PrPSc.