title: Prions disturb post-Golgi trafficking of membrane proteins.
abstract: Conformational conversion of normal cellular prion protein PrP(C) into pathogenic PrP(Sc) is central to the pathogenesis of prion diseases. However, the pathogenic mechanism remains unknown. Here we show that post-Golgi vesicular trafficking is significantly delayed in prion-infected N2a cells. Accordingly, cell surface expression of membrane proteins examined, including PrP(C), insulin receptor involved in neuroprotection, and attractin, whose mutation causes prion disease-like spongiform neurodegeneration, is reduced. Instead, they accumulate in the Golgi apparatus. PrP(Sc) is detected throughout endosomal compartments, being particularly abundant in recycling endosome. We also show reduced surface expression of PrP(C) and insulin receptor in prion-infected mouse brains well before the onset of disease. These results suggest that prion infection might impair post-Golgi trafficking of membrane proteins to the cell surface in neurons via PrP(Sc) accumulated in recycling endosome, and eventually induce neuronal dysfunctions associated with prion diseases.
authors.affiliation: Division of Molecular Neurobiology, The Institute for Enzyme Research (KOSOKEN), The University of Tokushima, 3-18-15 Kuramoto, Tokushima 770-8503, Japan.
authors.forename: Keiji
authors.initials: K
authors.lastname: Uchiyama
authors.forename: Naomi
authors.initials: N
authors.lastname: Muramatsu
authors.forename: Masashi
authors.initials: M
authors.lastname: Yano
authors.forename: Takeshi
authors.initials: T
authors.lastname: Usui
authors.forename: Hironori
authors.initials: H
authors.lastname: Miyata
authors.forename: Suehiro
authors.initials: S
authors.lastname: Sakaguchi
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism; D001710:Biotin / Q000378:metabolism; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D006224:Cricetinae; D004705:Endocytosis; D011992:Endosomes / Q000378:metabolism; D006056:Golgi Apparatus / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D018621:PrPC Proteins / Q000378:metabolism; D018620:PrPSc Proteins / Q000378:metabolism; D011328:Prions / Q000378:metabolism*; D021381:Protein Transport; D011972:Receptor, Insulin / Q000378:metabolism; D015398:Signal Transduction; D013347:Subcellular Fractions / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; C117928:Atrn protein, mouse; D007328:Insulin; D008565:Membrane Proteins; D018621:PrPC Proteins; D018620:PrPSc Proteins; D011328:Prions; D001710:Biotin; D011972:Receptor, Insulin