title: Nonenzymatic glycation at the N terminus of pathogenic prion protein in transmissible spongiform encephalopathies.
abstract: Transmissible spongiform encephalopathies (TSEs) are transmissible neurodegenerative diseases characterized by the accumulation of an abnormally folded prion protein, termed PrPSc, and the development of pathological features of astrogliosis, vacuolation, neuronal cell loss, and in some cases amyloid plaques. Although considerable structural characterization of prion protein has been reported, neither the method of conversion of cellular prion protein, PrPC, into the pathogenic isoform nor the post-translational modification processes involved is known. We report that in animal and human TSEs, one or more lysines at residues 23, 24, and 27 of PrPSc are covalently modified with advanced glycosylation end products (AGEs), which may be carboxymethyl-lysine (CML), one of the structural varieties of AGEs. The arginine residue at position 37 may also be modified with AGE, but not the arginine residue at position 25. This result suggests that nonenzymatic glycation is one of the post-translational modifications of PrP(Sc). Furthermore, immunostaining studies indicate that, at least in clinically affected hamsters, astrocytes are the first site of this glycation process.
authors.affiliation: Ilsong Institute of Life Science, College of Medicine, Hallym University, Anyang, Kyeonggi-Do, Republic of Korea.
authors.forename: Yeong-Gon
authors.initials: YG
authors.lastname: Choi
authors.forename: Jae-Il
authors.initials: JI
authors.lastname: Kim
authors.forename: Yong-Chul
authors.initials: YC
authors.lastname: Jeon
authors.forename: Seok-Joo
authors.initials: SJ
authors.lastname: Park
authors.forename: Eun-Kyoung
authors.initials: EK
authors.lastname: Choi
authors.forename: Richard
authors.initials: R
authors.lastname: Rubenstein
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Kascsak
authors.forename: Richard I
authors.initials: RI
authors.lastname: Carp
authors.forename: Yong-Sun
authors.initials: YS
authors.lastname: Kim
mesh_terms: D000818:Animals; D001120:Arginine / Q000737:chemistry; D001253:Astrocytes; D001667:Binding, Competitive; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D006031:Glycosylation; D006801:Humans; D007150:Immunohistochemistry; D007700:Kinetics; D008239:Lysine / Q000031:analogs & derivatives* / Q000737:chemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D010100:Oxygen / Q000378:metabolism; D043524:Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase / Q000737:chemistry; D010455:Peptides / Q000737:chemistry; D018620:PrPSc Proteins / Q000737:chemistry; D011233:Precipitin Tests; D017096:Prion Diseases / Q000378:metabolism*; D011328:Prions / Q000737:chemistry*; D020033:Protein Isoforms; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary
chemical_list: D010455:Peptides; D018620:PrPSc Proteins; D011328:Prions; D020033:Protein Isoforms; C048496:N(6)-carboxymethyllysine; D001120:Arginine; D043524:Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase; D008239:Lysine; D010100:Oxygen