14 Neuropathology of Prion Diseases

The discovery of mechanisms of nerve cell dysfunction, degeneration, and death in prion diseases acquired by infection, in dominantly inherited forms, and in sporadic (idiopathic) forms has gone hand in hand with the discovery of the prion and how prions are propagated. The generation of PrP-specific antibodies led to our first immunohistochemical study, in which we discovered that the amyloid plaques in experimental scrapie in Syrian hamsters contain protease-resistant PrP (Fig. 1A) (Bendheim et al. 1984; DeArmond et al. 1985). That finding convinced us that we had a unique opportunity to obtain a better understanding of the pathogenesis of scrapie in animals and the related human disorders that include sporadic, iatrogenic, and familial Creutzfeldt-Jakob disease (CJD), and the rare familial disorder Gerstmann-Straussler-Scheinker syndrome (GSS). The overall objective was to test the hypothesis that PrP Sc accumulation in the brain causes the clinically relevant neuronal dysfunction, vacuolation, and death that are the characteristics of prion diseases. The results of many studies have led to the unifying hypothesis that neuronal degeneration in spontaneous, infectious, and genetic prion diseases and the propagation of prions in those diseases are both related exclusively to abnormalities of PrP. Multiple investigators in Great Britain, Europe, Japan, and the US have contributed to our understanding of the mechanisms of CNS degeneration peculiar to prion diseases. We have attempted to identify and acknowledge their many contributions; however, the number of prion disease investigators is increasing logarithmically and, therefore, inevitably we will have missed some and apologize to them for that...