Prion diseases are progressive
neurodegenerative disorders affecting humans and other mammalian species. The term
prion, originally put forward to propose the concept that a
protein could be infectious, refers to PrPSc , a misfolded
isoform of the cellular
prion protein (PrPC ) that represents the pathogenetic hallmark of these disorders. The discovery that other
proteins characterized by misfolding and seeded aggregation can spread from cell to cell, similarly to PrPSc , has increased interest in
prion diseases. Among
neurodegenerative disorders, however,
prion diseases distinguish themselves for the broader phenotypic spectrum, the fastest
disease progression and the existence of infectious forms that can be transmitted through the exposure to diseased tissues via ingestion, injection or
transplantation. The main clinicopathological phenotypes of human
prion disease include
Creutzfeldt-Jakob disease, by far the most common, fatal
insomnia, variably
protease-sensitive prionopathy, and Gerstmann-Sträussler-Scheinker disease. However, clinicopathological manifestations extend even beyond those predicted by this classification. Because of their transmissibility, the phenotypic diversity of
prion diseases can also be propagated into syngenic hosts as
prion strains with distinct characteristics, such as incubation period, pattern of PrPSc distribution and regional severity of histopathological changes in the brain. Increasing evidence indicates that different PrPSc conformers, forming distinct ordered aggregates, encipher the phenotypic variants related to
prion strains. In this review, we summarize the most recent advances concerning the histo-molecular pathology of human
prion disease focusing on the phenotypic spectrum of the disease including co-pathologies, the characterization of
prion strains by experimental transmission and their correlation with the physicochemical properties of PrPSc aggregates.