Box 1. The cell biology of transmissible spongiform encephalopathies

From the following article:

Prions and their partners in crime

Byron Caughey & Gerald S. Baron

Nature 443, 803-810(19 October 2006)

doi:10.1038/nature05294

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As a GPI-anchored plasma-membrane glycoprotein (panel a), the PrPC polypeptide is synthesized in the endoplasmic reticulum (ER), processed in the Golgi apparatus and then carried, in its mature form, to the cell surface (panel b). PrPC is usually associated with detergent-resistant membrane subdomains known as rafts.

In cultured scrapie-infected cells, the generation of PrPres from PrPC occurs after the arrival of PrPC at the cell surface82, 83. This conversion is directly induced by pre-existing PrPres and apparent cofactors through an ill-defined templating mechanism that results in PrPC joining the inducing PrPres oligomer or polymer. Important modulators of this conversion include sulphated GAG-containing proteoglycans such as HSPG (Box 2), raft membrane lipids84 and LR/LRP16. The scrapie-associated conversion site for membrane-anchored wild-type PrPC seems to be on the cell surface and/or in endosomes that are drawn in from the cell surface82, 83, 85. However, PrPC released from the cell due to lack of a GPI anchor19 may be converted to extracellular deposits such as amyloid fibrils and plaques (Fig. 1). In familial TSE-associated mutant PrPC molecules, spontaneous folding abnormalities can occur in the endoplasmic reticulum and/or the Golgi apparatus (for a review see ref. 30).

Prions and their partners in crime 

Misfolded PrPC can be subject to the ER-associated degradation pathway (ERAD; panel b). Under conditions of proteasome inhibition, cytoplasmic forms of PrP aggregates associated with neurotoxicity (such as PrPcyto and aggresomes) have also been described22, 52, but the implications of these findings remain controversial. Furthermore, the mechanisms by which such aggregates are generated (for instance, the translocation of PrPres from the lumen of endocytic and lysosomal vesicles into cytosolic aggresomes, and the cause of proteasome inhibition) are unknown. The release of reactive oxygen species (ROS) from chemokine-activated microglial cells26 could contribute to ER stress and/or the ERAD process by inactivation of ER-chaperones86 (for example, protein disulphide isomerase (PDI) and GRP58), one of which has been shown to protect against prion neurotoxicity23. Excessive levels of misfolded proteins in the cytosol might impair proteasome function, either directly or after incorporation into aggresomes.

Once PrPres has been made, it can accumulate on the cell surface, in intracellular vesicles such as lysosomes or autophagosomes, or in extracellular deposits. PrPres and TSE infectivity can be released from cells in association with membrane-enclosed vesicles such as exosomes87. Uninfected neuronal cells can incorporate PrPres from the extracellular milieu by means of a mechanism that involves HSPG and LRP/LR10, 11, 58, 59, distribute it along neuritic pathways, and initiate propagation of new PrPres72. Panel c shows a pseudo-coloured image of cultured neuronal cells to which fluorescently tagged scrapie PrPres (red) has been added. During the infection process, the cells have taken up PrPres particles into acidic vesicles and transported them along the neurites to points of contact with other cells72.

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