NR AQQX
AU Arjona,A.; Simarro,L.; Islinger,F.; Nishida,N.; Manuelidis,L.
TI Two Creutzfeldt-Jakob disease agents reproduce prion protein-independent identities in cell cultures
QU Proceedings of the National Academy of Sciences of the United States of America 2004 Jun 8; 101(23): 8768-73
IA http://www.pnas.org/cgi/content/full/101/23/8768
PT journal article
AB Human Creutzfeldt-Jakob disease (CJD) and similar neurodegenerative diseases such as sheep scrapie are caused by a variety of related infectious agents. They are associated with abnormal host prion protein (PrP), which is assessed by limited proteolysis to yield resistant PrP bands (PrPres). Although PrPres has been posited as the infectious agent, purified PrPres itself is not infectious. To establish the independence of CJD agent characteristics from those of PrPres, two different mouse-passaged CJD strains were propagated in neuronal cell lines whose PrPres patterns differ markedly from each other and from those found in infected brain. In mouse brain, the fast CJD strain, FU, elicits many PrPres deposits, whereas the slow SY strain elicits few. Both strains evoked PrPres in cultured murine cells, although SY induced PrPres only transiently. PrPres patterns in FU- and SY-infected GT1 cells were identical, and were significantly different from those in brain and in N2a cells. Nevertheless, all FU-infected cell lines reproduced their original fast disease in mice, even after extensive subculture, whereas SY-infected cells produced only slow disease. These data indicate PrPres neither encodes nor alters agent-specific characteristics. PrPres was also a poor predictor of infectivity because SY cells that had lost PrPres were approximately 10-fold more infectious than PrPres-positive cultures. Furthermore, FU titers increased 650-fold, whereas PrPres remained constant. Passaged FU-infected cells had titers comparable to brain, and >30% of cells displayed abundant cytoplasmic PrPres aggregates that may trap agent. The continuous substantial replication of CJD in monotypic cells will further the discrimination of agent-specific molecules from pathological host responses to infection.
MH Animals; Brain/metabolism/pathology; Cell Line; Creutzfeldt-Jakob Syndrome/etiology/*metabolism; Glial Fibrillary Acidic Protein/metabolism; Humans; Mice; Prions/*metabolism; Research Support, U.S. Gov't, Non-P.H.S.; Research Support, U.S. Gov't, P.H.S.
AD Yale Medical School, 333 Cedar Street, Farnum Memorial Basement 11, New Haven, CT 06510, USA
SP englisch
PO USA