Uncontrolled SFK-mediated protein trafficking in prion and Alzheimer's disease

Abstract

Prions and Amyloid beta (Aβ) peptides induce synaptic damage via complex mechanisms that include the pathological alteration of intracellular signaling cascades. The host-encoded cellular prion protein (PrP^C) acts as a high-affinity cell surface receptor for both toxic species and it can modulate the endocytic trafficking of the N-methyl D-aspartate (NMDA) receptor and E-cadherin adhesive complexes via Src family kinases (SFKs). Interestingly, SFK-mediated control of endocytosis is a widespread mechanism used to regulate the activity of important transmembrane proteins, including neuroreceptors for major excitatory and inhibitory neurotransmitters. Here we discuss our recent work in zebrafish and accumulating evidence suggesting that subversion of this pleiotropic regulatory mechanism by Aβ oligomers and prions explains diverse neurotransmission deficits observed in human patients and mouse models of prion and Alzheimer's neurodegeneration. While Aβ, PrP^C and SFKs constitute potential therapeutic targets on their own, drug discovery efforts might benefit significantly from aiming at protein-protein interactions that modulate the endocytosis of specific SFK targets.

Keywords: Alzheimer disease; Aβ peptide; E-cadherin; NMDA receptor; Src family kinases; endocytosis; neurotransmission; prion protein; synaptic damage; zebrafish.

FIGURE 1.

Potential effect of Aβ and PrP^C on SFK-regulated trafficking of neuroreceptor and adhesion complexes. Aβ oligomers bind PrP^C on neuronal cell surfaces with high affinity, triggering the activation of SFKs, often through a transmembrane PrP^C partner (e.g. caveolin, mGluR5, NCAM, EGFR⁹). Apart from phosphorylating the disease-associated Tau protein and other cytosolic targets, SFKs can modulate the cell surface stability of numerous transmembrane proteins via endocytic tyrosine motifs at their cytoplasmic tails. Some of these, such as neuroreceptor subunits (NMDAR, AMPAR, GABA_AR and nAChR) and adhesion proteins (E- and N-cadherin), are directly involved in synaptic function and can potentially explain key pathological features of prion and Alzheimer's disease. SFKs control the trafficking of these transmembrane proteins by directly phosphorylating their endocytic motifs or by targeting components of their tyrosine endocytic machinery like AP-2 and clathrin. These modifications can result in either increased stability at the plasma membrane (gain of function) or protein internalization and degradation (loss of function). To date, experimental evidence for an influence of Aβ and PrP on this mechanism is only available for NMDAR and AJ complexes. In the case of the nAChR, Src kinase activity controls its trafficking but tyrosine endocytic motifs appear dispensable (as suggested by the question mark). Double arrows above the transmembrane target proteins indicate their relevance to prion or Alzheimer's disease.