NR AWLL
AU Orsi,A.; Fioriti,L.; Chiesa,R.; Sitia,R.
TI Conditions of ER stress favour the accumulation of cytosolic PrP
QU International Conference - Prion 2006: Strategies, advances and trends towards protection of society - 3.10.-6.10.2006, Torino, Italy, Lingotto Conference Centre - Poster sessions CE-38
PT Konferenz-Poster
AB After signal sequence-dependent targeting to the endoplasmic reticulum (ER)1, PrP undergoes several post-translational modifications, including glycosylation, disulfide bond formation and addition of a GPI anchor. As a result, multiple isoforms are generated. Owing to the intrinsic weakness of the PrP signal sequence, a fraction of newly synthesized molecules fails to translocate and localizes to the cytosol. The physio-pathologic role of this cytosolic isoform is debated. Here we show that in both cultured cell lines and primary neurons, ER stress conditions weaken PrP co-translational translocation, favouring accumulation of aggregation-prone cytosolic species, which retain the signal sequence but lack N-glycans and disulfides. Inhibition of proteasomes further increases the levels of cytosolic PrP. Over-expression of spliced XBP1 facilitates ER translocation, suggesting that downstream elements of the Ire1-XBP1 pathway are involved in PrP targeting. These studies reveal a link between ER stress and the formation of cytosolic PrP isoforms potentially endowed with novel signalling or cytotoxic functions.
AD A. Orsi, R. Sitia: Universita Vita-Salute San Raffaele - DiBiT Istituto Scientifico San Raffaele; Milano, Italy; L. Fioriti, R. Chiesa: Dulbecco Telethon Institute (DTI) and Istituto di Ricerche Farmacologiche Mario Negri; Milano, Italy. E-mail: orsi.andrea@hsr.it
SP englisch
PO Italien