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
• endocytosis
• NMDA receptor
• neurotransmission
• prion protein
• Src family kinases
• synaptic damage
• zebrafish

This article refers to:

DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST

No potential conflicts of interest were disclosed.

ACKNOWLEDGMENTS

Our special thanks to Dora and Jack for their continued support.

Funding

Work in the Málaga-Trillo lab is funded by PRODUCE-Innóvate Perú and the Universidad Peruana Cayetano Heredia. K. Ochs is supported by a PROMOS stipend from the DAAD.