The effects of the cellular and infectious prion protein on the neuronal adaptor protein X11α

Background: The neuronal adaptor protein X11α 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 X11α 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 X11α is examined.

Results: We show that X11α 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 X11α at a functional level. One of the effects of prion infection is lowered cellular SOD1 levels, here by knockdown of X11α we identify that the effect of PrP(Sc) on SOD1 can be reversed indicating that X11α is involved in prion disease pathogenesis.

Conclusions: A role for the cellular and infectious prion protein, PrP(C) and PrP(Sc), respectively, in regulating X11α is identified in this work.

General significance: Due to the multiple interacting partners of X11α, dysfunction or alteration in X11α will have a significant cellular effect. This work highlights the role of PrP(C) and PrP(Sc) in the regulation of X11α, and provides a new target pathway to control X11α and its related functions.