In animals and human, prions target and replicate in cells of neuronal and non-neuronal origin in a variety of tissues. As in the case for PrPSc-induced toxicity, the toxic potential of the S-amyloid structures was found to depend in part on the level of PrPC expression. A growing number of studies illustrate that on cell surface PrPC interacts with and mediates neurotoxic signaling of various b-sheet rich oligomers or fibrils formed by non-PrP proteins or peptides. These findings suggest that PrPC might be involved in mediating toxic signals in a number of neurodegenerative diseases. The results of the current studies support the idea that silencing of PrPC expression offers a valuable therapeutic strategy as it limits the toxic effects of large fibrils or small fibrillar fragments. PrPC dependence of the cellular response does not exclude the possibility that different signaling cascades are triggered by structurally different fibrils or particles, and that Thapsigargin fibril-triggered toxicity might involve multiple mechanisms. Sporadic Creutzfeldt-Jakob Disease is known to display substantial heterogeneity in neuropathological features including variations in lesion profile and PrPSc deposition. It would be difficult to explain the substantial phenotypic variations in pathology observed within the same class of neurodegenerative maladies, if one ignores conformational diversity of aggregated states and the possibility that each of these states exhibit the capacity of recruiting a variety of cytotoxic mechanisms. Nevertheless, extrapolating the relationships between molecular structure, size and cytotoxicity observed in cultured cells to the pathology in vivo needs to be considered with great caution because glial cells and astrocytes might neutralize aggregates of a certain size, protecting neuronal cells, or become activated and inflamed leading to additional neuronal damage. Considering that silencing of PrPC expression by shRNA did not restore cell viability completely, extracellular PrP fibrils might also trigger PrPC independent cytotoxic effects. This result is consistent with previous findings where extracellular PrP fibrils or oligomers were shown to exhibit toxicity in a PrPC-independent manner in primary neurons or animals. Because PrPC silencing abolished the toxic effect of R- and S-structures to a different extent, the role of PrPC-mediated versus PrPC independent signaling pathways Monensin sodium salt appears to depend on the structure of toxic aggregates.