Prions disturb post-Golgi trafficking of membrane proteins

• Published in: Nature communications Vol. 4; no. 1; p. 1846
• Main Authors: Uchiyama, Keiji, Muramatsu, Naomi, Yano, Masashi, Usui, Takeshi, Miyata, Hironori, Sakaguchi, Suehiro
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 14-05-2013; Nature Publishing Group
• Subjects: 631/80/313; 692/420; 692/699/375/1937; Animals; Antibodies, Monoclonal - metabolism; Biotin - metabolism; Blotting, Western; Brain - metabolism; Brain - pathology; Cell Line; Cell Membrane - metabolism; Cricetinae; Endocytosis; Endosomes - metabolism; Golgi Apparatus - metabolism; Humanities and Social Sciences; Humans; Insulin - metabolism; Male; Membrane Proteins - metabolism; Mice; Models, Biological; multidisciplinary; Prions - metabolism; Protein Transport; PrPC Proteins - metabolism; PrPSc Proteins - metabolism; Receptor, Insulin - metabolism; Science; Science (multidisciplinary); Signal Transduction; Subcellular Fractions - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms2873

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.
Prion protein accumulation in endosomal vesicles has been implicated in the progression of prion diseases. Uchiyama and colleagues infect neuronal cells with prion proteins and find that this delays post-Golgi vesicular trafficking of membrane proteins and impairs insulin signalling.