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The Journal of Neuroscience, August 6, 2003, 23(18):7183-7193

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Cytosolic Prion Protein in Neurons

Alexander Mironov, Jr,¹ Diane Latawiec,² Holger Wille,^2,3 Essia Bouzamondo-Bernstein,^2,4 Giuseppe Legname,^2,3 R. Anthony Williamson,⁶ Dennis Burton,⁶ Stephen J. DeArmond,^2,4 Stanley B. Prusiner,^2,3,5 and Peter J. Peters¹

¹The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands, ²Institute for Neurodegenerative Diseases, Departments of ³Neurology, ⁴Pathology and ⁵Biochemistry and Biophysics, University of California, San Francisco, California 94143, and ⁶Scripps Research Institute, La Jolla, California 92037

Localizing the cellular prion protein (PrP^C) in the brain is necessary for understanding the pathogenesis of prion diseases. However, the precise ultrastructural localization of PrP^C still remains enigmatic. We performed the first quantitative study of the ultrastructural localization of PrP^C in the mouse hippocampus using high-resolution cryoimmunogold electron microscopy. PrP^C follows the standard biosynthetic trafficking pathway with a preferential localization in late endosomal compartments and on the plasma membrane of neurons and neuronal processes. PrP^C is found with the same frequency within the synaptic specialization and perisynaptically, but is almost completely excluded from synaptic vesicles. Unexpectedly, PrP is also found in the cytosol in subpopulations of neurons in the hippocampus, neocortex, and thalamus but not the cerebellum. Cytosolic PrP may have altered susceptibility to aggregation, suggesting that these neurons might play a significant role in the pathogenesis of prion diseases, in particular those mammals harboring mutant PrP genes.

Key words: prion protein; hippocampus; immunogold; localization; membrane; cytosolic

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Received Nov. 1, 2002; revised Feb. 28, 2003; accepted Mar. 18, 2003.

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