Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
A nine amino acid domain is essential for mutant prion protein toxicity.
Westergard L
,
Turnbaugh JA
,
Harris DA
.
???displayArticle.abstract???
Transgenic mice expressing prion protein (PrP) molecules with several different internal deletions display spontaneous neurodegenerative phenotypes that can be dose-dependently suppressed by coexpression of wild-type PrP. Each of these deletions, including the largest one (Δ32-134), retains 9 aa immediately following the signal peptide cleavage site (residues 23-31; KKRPKPGGW). These residues have been implicated in several biological functions of PrP, including endocytic trafficking and binding of glycosaminoglycans. We report here on our experiments to test the role of this domain in the toxicity of deleted forms of PrP. We find that transgenic mice expressing Δ23-134 PrP display no clinical symptoms or neuropathology, in contrast to mice expressing Δ32-134 PrP, suggesting that residues 23-31 are essential for the toxic phenotype. Using a newly developed cell culture assay, we narrow the essential region to amino acids 23-26, and we show that mutant PrP toxicity is not related to the role of the N-terminal residues in endocytosis or binding to endogenous glycosaminoglycans. However, we find that mutant PrP toxicity is potently inhibited by application of exogenous glycosaminoglycans, suggesting that the latter molecules block an essential interaction between the N terminus of PrP and a membrane-associated target site. Our results demonstrate that a short segment containing positively charged amino acids at the N terminus of PrP plays an essential role in mediating PrP-related neurotoxicity. This finding identifies a protein domain that may serve as a drug target for amelioration of prion neurotoxicity.
Aguzzi,
Mammalian prion biology: one century of evolving concepts.
2004, Pubmed
Aguzzi,
Mammalian prion biology: one century of evolving concepts.
2004,
Pubmed
Ashok,
Selective processing and metabolism of disease-causing mutant prion proteins.
2009,
Pubmed
Atarashi,
Deletion of N-terminal residues 23-88 from prion protein (PrP) abrogates the potential to rescue PrP-deficient mice from PrP-like protein/doppel-induced Neurodegeneration.
2003,
Pubmed
Baeuerle,
Chlorate--a potent inhibitor of protein sulfation in intact cells.
1986,
Pubmed
Baumann,
Lethal recessive myelin toxicity of prion protein lacking its central domain.
2007,
Pubmed
Borchelt,
A vector for expressing foreign genes in the brains and hearts of transgenic mice.
1996,
Pubmed
Brimacombe,
Characterization and polyanion-binding properties of purified recombinant prion protein.
1999,
Pubmed
Büeler,
Normal development and behaviour of mice lacking the neuronal cell-surface PrP protein.
1992,
Pubmed
Cardin,
Molecular modeling of protein-glycosaminoglycan interactions.
1989,
Pubmed
Caughey,
Sulfated polyanion inhibition of scrapie-associated PrP accumulation in cultured cells.
1993,
Pubmed
Chen,
Interaction between human prion protein and amyloid-beta (Abeta) oligomers: role OF N-terminal residues.
2010,
Pubmed
Chen,
Truncated forms of the human prion protein in normal brain and in prion diseases.
1995,
Pubmed
Chiesa,
Neurological illness in transgenic mice expressing a prion protein with an insertional mutation.
1998,
Pubmed
Christensen,
A deleted prion protein that is neurotoxic in vivo is localized normally in cultured cells.
2009,
Pubmed
Doh-ura,
Treatment of transmissible spongiform encephalopathy by intraventricular drug infusion in animal models.
2004,
Pubmed
Drisaldi,
Genetic mapping of activity determinants within cellular prion proteins: N-terminal modules in PrPC offset pro-apoptotic activity of the Doppel helix B/B' region.
2004,
Pubmed
Fischer,
Prion protein (PrP) with amino-proximal deletions restoring susceptibility of PrP knockout mice to scrapie.
1996,
Pubmed
Gu,
Identification of cryptic nuclear localization signals in the prion protein.
2003,
Pubmed
Hachiya,
Microtubules-associated intracellular localization of the NH2-terminal cellular prion protein fragment.
2004,
Pubmed
Hachiya,
Anterograde and retrograde intracellular trafficking of fluorescent cellular prion protein.
2004,
Pubmed
Harris,
New insights into prion structure and toxicity.
2006,
Pubmed
Li,
Neonatal lethality in transgenic mice expressing prion protein with a deletion of residues 105-125.
2007,
Pubmed
Mallucci,
Post-natal knockout of prion protein alters hippocampal CA1 properties, but does not result in neurodegeneration.
2002,
Pubmed
Mallucci,
Targeting cellular prion protein reverses early cognitive deficits and neurophysiological dysfunction in prion-infected mice.
2007,
Pubmed
Mallucci,
Depleting neuronal PrP in prion infection prevents disease and reverses spongiosis.
2003,
Pubmed
Manson,
129/Ola mice carrying a null mutation in PrP that abolishes mRNA production are developmentally normal.
1994,
Pubmed
Massignan,
A novel, drug-based, cellular assay for the activity of neurotoxic mutants of the prion protein.
2010,
Pubmed
Nunziante,
Essential role of the prion protein N terminus in subcellular trafficking and half-life of cellular prion protein.
2003,
Pubmed
,
Xenbase
Ostapchenko,
The polybasic N-terminal region of the prion protein controls the physical properties of both the cellular and fibrillar forms of PrP.
2008,
Pubmed
Pan,
Cell-surface prion protein interacts with glycosaminoglycans.
2002,
Pubmed
Parkin,
Cellular prion protein regulates beta-secretase cleavage of the Alzheimer's amyloid precursor protein.
2007,
Pubmed
Pasupuleti,
Antimicrobial activity of human prion protein is mediated by its N-terminal region.
2009,
Pubmed
Prusiner,
Prions.
1998,
Pubmed
Shmerling,
Expression of amino-terminally truncated PrP in the mouse leading to ataxia and specific cerebellar lesions.
1998,
Pubmed
Shyng,
A prion protein cycles between the cell surface and an endocytic compartment in cultured neuroblastoma cells.
1993,
Pubmed
Shyng,
A glycolipid-anchored prion protein is endocytosed via clathrin-coated pits.
1994,
Pubmed
Shyng,
The N-terminal domain of a glycolipid-anchored prion protein is essential for its endocytosis via clathrin-coated pits.
1995,
Pubmed
Shyng,
Sulfated glycans stimulate endocytosis of the cellular isoform of the prion protein, PrPC, in cultured cells.
1995,
Pubmed
Solforosi,
Toward molecular dissection of PrPC-PrPSc interactions.
2007,
Pubmed
Solomon,
An N-terminal polybasic domain and cell surface localization are required for mutant prion protein toxicity.
2011,
Pubmed
Solomon,
Prion neurotoxicity: insights from prion protein mutants.
2010,
Pubmed
Solomon,
Neurotoxic mutants of the prion protein induce spontaneous ionic currents in cultured cells.
2010,
Pubmed
Sunyach,
The mechanism of internalization of glycosylphosphatidylinositol-anchored prion protein.
2003,
Pubmed
Supattapone,
Identification of two prion protein regions that modify scrapie incubation time.
2001,
Pubmed
Taubner,
Structure of the flexible amino-terminal domain of prion protein bound to a sulfated glycan.
2010,
Pubmed
Taylor,
Assigning functions to distinct regions of the N-terminus of the prion protein that are involved in its copper-stimulated, clathrin-dependent endocytosis.
2005,
Pubmed
Taylor,
Glypican-1 mediates both prion protein lipid raft association and disease isoform formation.
2009,
Pubmed
Wadia,
Pathologic prion protein infects cells by lipid-raft dependent macropinocytosis.
2008,
Pubmed
Warner,
Identification of the heparan sulfate binding sites in the cellular prion protein.
2002,
Pubmed
Yoshikawa,
Dominant-negative effects of the N-terminal half of prion protein on neurotoxicity of prion protein-like protein/doppel in mice.
2008,
Pubmed
Zulianello,
Dominant-negative inhibition of prion formation diminished by deletion mutagenesis of the prion protein.
2000,
Pubmed
