title: 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 (PrPC) 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, PrPCand 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.
authors.affiliation: a Department of Biology , Universidad Peruana Cayetano Heredia , Lima , Perú.
authors.forename: Edward
authors.initials: E
authors.lastname: Málaga-Trillo
authors.affiliation: a Department of Biology , Universidad Peruana Cayetano Heredia , Lima , Perú.|b Department of Biology , University of Konstanz , Konstanz , Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Ochs
mesh_terms: D000544:Alzheimer Disease / Q000201:enzymology / Q000378:metabolism* / Q000628:therapy; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D015820:Cadherins / Q000378:metabolism; D004705:Endocytosis; D006801:Humans; D051379:Mice; D017096:Prion Diseases / Q000201:enzymology / Q000378:metabolism* / Q000628:therapy; D021381:Protein Transport; D015398:Signal Transduction; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D015820:Cadherins; D019061:src-Family Kinases
keywords: Alzheimer disease; Aβ peptide; E-cadherin; NMDA receptor; Src family kinases; endocytosis; neurotransmission; prion protein; synaptic damage; zebrafish