title: Chondroitin Sulfate Accelerates Trans-Golgi-to-Surface Transport of Proteoglycan Amyloid Precursor Protein.
abstract: The amyloid precursor protein (APP) is a membrane protein implicated in the pathogenesis of Alzheimer's disease. APP is a part-time proteoglycan, as splice variants lacking exon 15 are modified by a chondroitin sulfate glycosaminoglycan (GAG) chain. Investigating the effect of the GAG chain on the trafficking of APP in non-polarized cells, we found it to increase the steady-state surface-to-intracellular distribution, to reduce the rate of endocytosis and to accelerate transport kinetics from the trans-Golgi network (TGN) to the plasma membrane. Deletion of the cytosolic domain resulted in delayed surface arrival of GAG-free APP, but did not affect the rapid export kinetics of the proteoglycan form. Protein-free GAG chains showed the same TGN-to-cell surface transport kinetics as proteoglycan APP. Endosome ablation experiments were performed to distinguish between indirect endosomal and direct pathways to the cell surface. Surprisingly, TGN-to-cell surface transport of both GAG-free and proteoglycan APP was found to be indirect via transferrin-positive endosomes. Our results show that GAGs act as alternative sorting determinants in cellular APP transport that are dominant over cytoplasmic signals and involve distinct sorting mechanisms.
authors.affiliation: Biozentrum, University of Basel, Klingelbergstrasse 70, CH-4056, Basel, Switzerland.
authors.forename: Deyan
authors.initials: D
authors.lastname: Mihov
authors.affiliation: Biozentrum, University of Basel, Klingelbergstrasse 70, CH-4056, Basel, Switzerland.
authors.forename: Eva
authors.initials: E
authors.lastname: Raja
authors.affiliation: Biozentrum, University of Basel, Klingelbergstrasse 70, CH-4056, Basel, Switzerland.
authors.forename: Martin
authors.initials: M
authors.lastname: Spiess
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism*; D011508:Chondroitin Sulfate Proteoglycans / Q000378:metabolism*; D002809:Chondroitin Sulfates / Q000378:metabolism*; D011992:Endosomes / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D011499:Protein Processing, Post-Translational; D021381:Protein Transport; D021601:trans-Golgi Network / Q000378:metabolism*
chemical_list: D016564:Amyloid beta-Protein Precursor; D011508:Chondroitin Sulfate Proteoglycans; D002809:Chondroitin Sulfates
keywords: amyloid precursor protein; chondroitin sulfate; glycosaminoglycan; protein transport; proteoglycan