The interaction between cytoplasmic prion protein and the hydrophobic lipid core of membrane correlates with neurotoxicity.
Prion protein (PrP), normally a cell surface protein, has been detected in the cytosol of a subset of neurons. The appearance of PrP in the cytosol could result from either retro-translocation of misfolded PrP from the endoplasmic reticulum (ER) or impaired import of PrP into the ER. Transgenic mice expressing cytoplasmic PrP (cyPrP) developed neurodegeneration in cerebellar granular neurons, although no detectable pathology was observed in other brain regions. In order to understand why granular neurons in the cerebellum were most susceptible to cyPrP-induced degeneration, we investigated the subcellular localization of cyPrP. Interestingly, we found that cyPrP is membrane-bound. In transfected cells, it binds to the ER and plasma/endocytic vesicular membranes. In transgenic mice, it is associated with synaptic and microsomal membranes. Furthermore, the cerebellar neurodegeneration in transgenic mice correlates with the interaction between cyPrP and the hydrophobic lipid core of the membrane but not with either the aggregation status or the dosage of cyPrP. These results suggest that lipid membrane perturbation could be a cellular mechanism for cyPrP-induced neurotoxicity and explain the seemingly conflicting results concerning cyPrP.
Wang
Xinhe
X
Department of Molecular and Cellular Biochemistry, Ohio State University, Columbus, Ohio 43210.
Wang
Fei
F
Department of Molecular and Cellular Biochemistry, Ohio State University, Columbus, Ohio 43210.
Arterburn
Linnea
L
Department of Molecular and Cellular Biochemistry, Ohio State University, Columbus, Ohio 43210.
Wollmann
Robert
R
Department of Pathology, University of Chicago, Chicago, Illinois 60637.
Ma
Jiyan
J
Department of Molecular and Cellular Biochemistry, Ohio State University, Columbus, Ohio 43210. Electronic address: ma.131@osu.edu.
D000818:Animals; D001921:Brain / Q000166:cytology / Q000378:metabolism; D002460:Cell Line; D002462:Cell Membrane / Q000737:chemistry* / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism*; D005786:Gene Expression Regulation; D057927:Hydrophobic and Hydrophilic Interactions; D008051:Lipid Bilayers / Q000737:chemistry* / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D011328:Prions / Q000378:metabolism* / Q000633:toxicity*; D011485:Protein Binding
D008051:Lipid Bilayers; D011328:Prions