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 Prion Pathway

Transmissible spongiform encephalopathies (TSE) (prion disease) are a group of fatal neurodegenerative diseases that include scrapie in dogs and sheep, bovine spongiform encephalopathy (BSE) (Mad Cow disease), and the human diseases; Creutzfeldt-Jakob disease (CJD), kuru, Gertsmann–Straussler–Scheinker syndrome, and fatal familial insomnia. TSE species specific diseases are transmitted by prions, proteinaceous infectious particles composed of a protease-resistant PrP protein isoform (PrP-res, PrP-sc).

PrP (PrPc) is a naturally occurring single gene derived glycoprotein that exists in cytoplasmic and membrane associated forms. TSE diseases are associated with a modified form of PrPc generally referred to as PrP-res (resistant) or PrPsc (derived from scrapie infected tissue). PrP-res and PrPc have the same primary sequence but they differ in their secondary and tertiary structure. PrPc has more a-helix structure versus PrP-res. PrP-res isoform contains more b-sheet structure. PrPc binds cupric copper. PrP-res does not bind copper. PrP-res is more protease resistant, and less soluble the PrPc. PrPc can be released from its GPI-membrane anchor by phosphoinositol phospholipase C (PI-PLC). PrP-res is resistant to PI-PLC.

Transmission of TSE is associated with the transfer of prions from infected cells or materials to target cells by a process that may involve binding to glucosaminoglycans (GAG). Internalized prions, which contain PrP-res isoforms, provide nucleation-sites to which normal PrPc proteins can bind. The prions are able to convert the PrPc to PrP-res isoform. Under appropriate conditions, the conversion of PrPc to PrP-res is cumulative and results in the formation of ubiquitin-proteosome resistant aggresomes. The formation of these aggresomes by conversion of normal PrPc to PrP-res is slow, but the eventual accumulation of PrP-res isoform containing aggresomes correlates with the induction of apoptosis via a caspase 8 and caspase-3 dependent pathway. TSE diseases are essentially protein miss-folding diseases that induce apoptosis in susceptible cells.