Fishing for prion protein function

Abstract

The prion protein is infamous for its role in devastating neurological diseases, but its normal, physiological function has remained mysterious. A new study uses the experimentally tractable zebrafish model to obtain fresh clues to this puzzle.

Figure 1. A Role for PrP^C Function in Prion Diseases

PrP^C on the cell surface performs its normal function by associating with a hypothetical transmembrane interactor (“X”). In the disease state, PrP^Sc (or a misfolded intermediate) initiates a toxic signal by associating with different interactors (“Y” or “Z”), possibly as a result of oligomerization.

Figure 2. Two Roles for PrP in Cell Adhesion

(A) In wild-type zebrafish (left), PrP-1 promotes proper delivery of E-cadherin from the Golgi to the plasma membrane (PM), possibly via activation of a signal transduction cascade involving Src-family tyrosine kinases. In morphant fish lacking PrP-1 (right), E-cadherin accumulates in intracellular vesicles, resulting in reduced delivery to the plasma membrane. As a result, Ca⁺²-dependent, cadherin-mediated cell adhesion is impaired. (B) PrP molecules on adjacent cells undergo homophilic interactions that promote cell adhesion in a Ca⁺²-independent manner, at the same time generating an intracellular signal involving tyrosine phosphorylation. The PrP functions depicted in the two panels of this figure could be linked, if the intracellular signal generated by homophilic binding of PrP molecules (B) regulates cadherin trafficking (A).