Molecular biology of prion protein and its first homologous protein

Conformational conversion of the normal cellular isoform of prion protein, PrPC, a glycoprotein anchored to the cell membrane by a glycosylphosphatidylinositol moiety, into the abnormally folded, amyloidogenic prion protein, PrPSc, plays a pivotal role in the pathogenesis of prion diseases. It has been suggested that PrPC might be functionally disturbed by constitutive conversion to PrPSc due to either the resulting depletion of PrPC or the dominant negative effects of PrPSc on PrPC or both. Consistent with this, we and others showed that mice devoid of PrPC (PrP-/-) spontaneously developed abnormal phenotypes very similar to the neurological abnormalities of prion diseases, supporting the concept that functional loss of PrPC might at least be partly involved in the pathogenesis of the diseases. However, no neuronal cell death could be detected in PrP-/- mice, indicating that the functional loss of PrPC alone might not be enough to induce neuronal cell death, one of major pathological hallmarks of prion diseases. Interestingly, it was recently shown that the first identified PrP-like protein, termed PrPLP/Doppel (Dpl), is neurotoxic in the absence of PrPC, causing Purkinje cell degeneration in the cerebellum of mice. Although it is not understood if PrPSc could have a neurotoxic potential similar to PrPLP/ Dpl, it is very interesting to speculate that accumulation of PrPSc and the functional disturbance of PrPC, both of which are caused by constitutive conversion, might be required for the neurodegeneration in prion diseases.