Function of Prion Protein and the Family Member, Shadoo.

Lowering cellular prion protein (PrPC) levels in the brain is predicted to be a powerful therapeutic strategy for the prion disease. PrPC may act as an antiapoptotic agent by blocking some of the internal environmental factors that initiate apoptosis. Prion protein (PrP)-knockout methods provide powerful indications on the neuroprotective function of PrPC. Using PrPC-knockout cell lines, the inhibition of apoptosis through stress inducible protein1 (STI1) is mediated by PrPC-dependent superoxide dismutase (SOD) activation. Besides, PrP-knockout exhibited wide spread alterations of oscillatory activity in the olfactory bulb as well as altered paired-pulse plasticity at the dendrodendric synapse. Both the behavioural and electro-physiological phenotypes could be rescued by neuronal PrPC expression. Neuprotein Shadoo (Sho), similarly to PrPC, can prevent neuronal cell death induced by the expression of PrP△HD mutants, an artificial PrP mutant devoid of internal hydrophobic domain. Sho can efficiently protect cells against exito-toxin-induced cell death by glutamates. Sho and PrP seem to be dependent on similar domains, in particular N-terminal (N), and their internal hydrophobic domain. Sho△N and Sho△HD displayed a reduced stress-protective activity but are complex glycosylated and attached to the outer leaflet of the plasma membrane via glycosylphosphatidylinositol (GPI) anchor indicating that impaired activity is not due to incorrect cellular trafficking. In Sho, over-expressed mice showed large amyloid plaques not seen in wild-type mice. However, Shadoo is not a major modulator of abnormal prion protein (PrPSc) accumulation. Sho and PrP share a stress-protective activity. The ability to adopt a toxic conformation of PrPSc seems to be specific for PrP.