The effects of the cellular and infectious prion protein on the neuronal adaptor protein X11alpha

BACKGROUND: The neuronal adaptor protein X11alpha is a multidomain protein with a phosphotyrosine binding (PTB) domain, two PDZ (PSD_95, Drosophila disks-large, ZO-1) domains, a Munc Interacting (MI) domain and a CASK interacting region. Amongst its functions is a role in the regulation of the abnormal processing of the amyloid precursor protein (APP). It also regulates the activity of Cu/Zn Superoxide dismutase (SOD1) through binding with its chaperone the copper chaperone for SOD1. How X11alpha production is controlled has remained unclear. METHODS: Using the neuroblastoma cell line, N2a, and knockdown studies, the effect of the cellular and infectious prion protein, PrP(C) and PrP(Sc), on X11alpha is examined. RESULTS: We show that X11alpha expression is directly proportional to the expression of PrP(C), whereas its levels are reduced by PrP(Sc). We also show PrP(Sc) to affect X11alpha at a functional level. One of the effects of prion infection is lowered cellular SOD1 levels, here by knockdown of X11alpha we identify that the effect of PrP(Sc) on SOD1 can be reversed indicating that X11alpha is involved in prion disease pathogenesis. CONCLUSIONS: A role for the cellular and infectious prion protein, PrP(C) and PrP(Sc), respectively, in regulating X11alpha is identified in this work. GENERAL SIGNIFICANCE: Due to the multiple interacting partners of X11alpha, dysfunction or alteration in X11alpha will have a significant cellular effect. This work highlights the role of PrP(C) and PrP(Sc) in the regulation of X11alpha, and provides a new target pathway to control X11alpha and its related functions.