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At this point, there are more questions than answers with regard to the pathophysiology of prion disorders. Although it is clear that host PrPC is required for the development of disease, the precise mechanism by which PrPC is converted to PrPSc or the biochemical pathways leading to neuronal damage remain unclear. Several triggers of prion-associated neuropathology have been proposed, including toxicity by PrPSc deposits, inherent toxicity of cytosolic PrP, initiation of pathogenic signals by C-transmembrane PrP, activation of the caspase pathway by PrPSc or PrPC, interference in transcription by association of PrPSc with chromatin in the nucleus, and several other equally important mechanisms supported by experimental evidence. In some instances, impaired proteasomal function contributes to the disease process, in others it does not. Converging evidence suggests that prion disorders are not the result of protein aggregation alone, but a combination of aberrant PrP metabolism and a failure of the cellular quality control mechanisms to cope. Thus, mis-metabolism of PrP and its eventual aggregation, and an overwhelmed chaperone and proteasomal response may precipitate these disorders. Such conditions have a greater propensity to occur with advanced age, explaining the late onset of these disorders despite the presence of germ-line mutations in certain instances. Accumulation of misfolded PrP may result in further deterioration of proteasomal function and an autocatalytic accumulation of misfolded forms. Although the cell death pathways activated by the culmination of these events are not entirely clear, research in the development of strategies that optimize or enhance the cellular quality control mechanisms including proteasomal function may help in the prevention of prion disorders [ABSTRACT FROM AUTHOR]