Prion-induced neuronal damage--the mechanisms of neuronal destruction in the subacute spongiform encephalopathies.

Prion diseases are characterized by the accumulation of a specific disease-associated isoform of the prion protein (PrP), termed PrPSc, which is the main, if not the only, component of the infectious agent termed prion. PrPSc is derived by an autocatalytic post-translational process involving conformational changes from the normal host-encoded isoform of the prion protein, termed PrPC. PrPC is a copper-binding glycoprotein attached to the cell membrane of neurons and other cells by means of a GPI anchor. The pattern of neurodegeneration differs between variants of prion disease and is related to the pattern of PrPSc deposition and differences in susceptibility of different cell types to the disease process. The pattern of PrPSc deposition depends on the strain of the agent and the PrP genotype of the host. Strain properties of prions appear to be related to different pathological conformations of PrPSc. Neuronal cell death is a salient feature in the pathology of prion diseases. Histological and electron microscopical studies have shown that cell death in prion disease occurs by apoptosis. Apoptosis of neuronal cells can also be induced in vitro by exposure to PrPSc or a neurotoxic peptide fragment corresponding to amino acids 106-126 of human prion protein (PrP106-126). Both in vitro and in vivo, the toxicity of PrPSc and PrP fragments appears to depend on neuronal expression of PrPC and on microglial activation. Activated microglial cells release pro-inflammatory cytokines and reactive oxygen species. Cell culture experiments suggest an important role of microglia-mediated oxidative stress in the induction of neuronal cell death. Only limited data are available on direct effects of PrPSc on neuronal cells. Potential effects include increased formation of an aberrant transmembrane form of PrP, termed CtmPrP, and changes in plasma membrane properties. In addition to direct and indirect toxic effects of PrPSc, a loss of function of PrPC may contribute to neuronal cell death. Potential mechanisms include disturbances in cerebral copper metabolism and antioxidative defense mechanisms. A better understanding of the pathogenesis of neuronal cell death in prion diseases may also have important therapeutic implications in the future.