Molecular biology of prion protein and its first homologous protein

Abstract

Conformational conversion of the normal cellular isoform of prion protein, PrP^C, a glycoprotein anchored to the cell membrane by a glycosylphosphatidylinositol moiety, into the abnormally folded, amyloidogenic prion protein, PrP^Sc, plays a pivotal role in the pathogenesis of prion diseases. It has been suggested that PrP^C might be functionally disturbed by constitutive conversion to PrP^Sc due to either the resulting depletion of PrP^C or the dominant negative effects of PrP^Sc on PrP^C or both. Consistent with this, we and others showed that mice devoid of PrP^C (PrP-/-) spontaneously developed abnormal phenotypes very similar to the neurological abnormalities of prion diseases, supporting the concept that functional loss of PrP^C 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 PrP^C 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 PrP^C, causing Purkinje cell degeneration in the cerebellum of mice. Although it is not understood if PrP^Sc could have a neurotoxic potential similar to PrPLP/Dpl, it is very interesting to speculate that accumulation of PrP^Sc and the functional disturbance of PrP^C, both of which are caused by constitutive conversion, might be required for the neurodegeneration in prion diseases. J. Med. Invest. 54: 211-223, August, 2007