NR ATGB
AU Saghafi,S.; Spilman,P.; Tanz,Z.; Schreiber,S.S.; Prusiner,S.B.; DeArmond,S.J.; Lingappa,V.R.
TI PrP Topology as a Determinant of Pro- or Anti-Apoptotic Functions
QU International Conference - Prion 2005: Between fundamentals and society's needs - 19.10.-21.10.2005, Congress Center Düsseldorf - Oral sessions ORAL-32
PT Konferenz-Vortrag
AB The function of the cellular prion protein (PrPc) has remained enigmatic, as both pro- and anti-apoptotic functions have been proposed. Our in vivo data suggests that PrPc consists of two topological isoforms, namely the type II transmembrane isoform termed CtmPrP and the fully translocated isoform which is tethered to the cell-surface termed SecPrP, which reveal opposing functions. CtmPrP over-expressing mice undergo spontaneous neurodegeneration as a result of increased apoptosis. Further investigation in cultured cells suggests that CtmPrP may be triggering a Bax and Caspase 3 associated apoptotic pathway. These results support the hypothesis that CtmPrP is the neurotoxic agent in infectious prion disease. In contrast to CtmPrP, SecPrP displays a neuroprotective function in an excitotoxicity model system. Transgenic mice expressing a PrP mutant that is only expressed in the SecPrP isoform also show more protection than wild-type PrP expressing mice. In contrast, mice favouring CtmPrP expression are highly vulnerable and display severe apoptosis. When mice favoring SecPrP are challenged with PrPsc they remain asymptomatic well after wild-type mice are terminally ill, despite having accumulated substantial amounts of PrPsc. The mutation that severely reduces the generation of CtmPrP, also substantially attenuates disease progression. The conversion of SecPrP to PrPsc suggests that loss of neuroprotective SecPrP may be an additional contributor in pathogenesis. Therefore our data lead to the conclusion that infectious prion disease is both a result of CtmPrP gain of function and loss of SecPrP function.
IN Fehlen einer Zelle bestimmte Faktoren, dann werden im ER transmembrane Prionproteine (CtmPrP) gebildet [AFGU], die eine Apoptose der Zelle fördern. Im Gegensatz zu dieser abnormen Form schützt das normale, über einen GPI-Anker an der Zellaußenseite hängende Prionprotein die Zelle. Bildet ein Mensch oder ein anderes Tier zu wenig dieser für eine korrekte Positionierung auf der Zellaußenseite erforderlichen Faktoren, dann wird er/es im Falle einer TSE-Infektion besonders früh erkranken. Das durch außerhalb des Prionproteingens liegende Faktoren beeinflusste Verhältnis von CtmPrP und PrPc bestimmt auch darüber, ab wann die PrP-Akkumulation zum Absterben von Neuronen führt.
AD S.Saghafi, P.Spilman, S.B.Prusiner, S.J.DeArmond, V.R.Lingappa, UCSF, USA; Z.Tanz, S.S.Schreiber, UCI, USA
SP englisch
PO Deutschland