title: N(ε)-Carboxymethyl Modification of Lysine Residues in Pathogenic Prion Isoforms.
abstract: The most prominent hallmark of prion diseases is prion protein conversion and the subsequent deposition of the altered prions, PrP(Sc), at the pathological sites of affected individuals, particularly in the brain. A previous study has demonstrated that the N-terminus of the pathogenic prion isoform (PrP(Sc)) is modified with advanced glycation end products (AGEs), most likely at one or more of the three Lys residues (positions 23, 24, and 27) in the N-terminus (23KKRPKP28). The current study investigated whether N(ε)-(carboxymethyl)lysine (CML), a major AGE form specific to Lys residues produced by nonenzymatic glycation, is an AGE adduct of the N-terminus of PrP(Sc). We show that CML is linked to at least one Lys residue at the N-terminus of PrP(Sc) in 263K prion-infected hamster brains and at least one of the eight Lys residues (positions 101, 104, 106, 110, 185, 194, 204, and 220) in the proteinase K (PK)-resistant core region of PrP(Sc). The nonenzymatic glycation of the Lys residue(s) of PrP(Sc) with CML likely occurs in the widespread prion-deposit areas within infected brains, particularly in some of the numerous tyrosine hydroxylase-positive thalamic and hypothalamic nuclei. CML glycation does not occur in PrP(C) but is seen in the pathologic PrP(Sc) isoform. Furthermore, the modification of PrP(Sc) with CML may be closely involved in prion propagation and deposition in pathological brain areas.
authors.affiliation: Ilsong Institute of Life Science, Hallym University, 1605-4 Gwanyangdong, Dongan-gu, Anyang, Gyeonggi-do, 431-060, South Korea.
authors.forename: Yeong-Gon
authors.initials: YG
authors.lastname: Choi
authors.affiliation: Ilsong Institute of Life Science, Hallym University, 1605-4 Gwanyangdong, Dongan-gu, Anyang, Gyeonggi-do, 431-060, South Korea.
authors.forename: Hae-Young
authors.initials: HY
authors.lastname: Shin
authors.affiliation: Department of Food Science and Nutrition, Bukyong National University, Busan, South Korea.
authors.forename: Jae-Il
authors.initials: JI
authors.lastname: Kim
authors.affiliation: Ilsong Institute of Life Science, Hallym University, 1605-4 Gwanyangdong, Dongan-gu, Anyang, Gyeonggi-do, 431-060, South Korea.
authors.forename: Eun-Kyoung
authors.initials: EK
authors.lastname: Choi
authors.affiliation: New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY, 10314, USA.
authors.forename: Richard I
authors.initials: RI
authors.lastname: Carp
authors.affiliation: Ilsong Institute of Life Science, Hallym University, 1605-4 Gwanyangdong, Dongan-gu, Anyang, Gyeonggi-do, 431-060, South Korea. yskim@hallym.ac.kr.|Department of Microbiology, College of Medicine, Hallym University, 1 Hallymdaehak-gil, Chuncheon, Gangwon-do, 200-702, South Korea. yskim@hallym.ac.kr.
authors.forename: Yong-Sun
authors.initials: YS
authors.lastname: Kim
mesh_terms: D000818:Animals; D002451:Cell Compartmentation; D002462:Cell Membrane / Q000378:metabolism; D019286:Endopeptidase K / Q000378:metabolism; D017127:Glycation End Products, Advanced / Q000378:metabolism; D006031:Glycosylation; D008239:Lysine / Q000031:analogs & derivatives* / Q000378:metabolism; D008297:Male; D008647:Mesocricetus; D009474:Neurons / Q000378:metabolism; D018620:PrPSc Proteins / Q000737:chemistry / Q000378:metabolism*; D020033:Protein Isoforms / Q000378:metabolism; D012995:Solubility; D013788:Thalamus / Q000378:metabolism / Q000473:pathology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D017127:Glycation End Products, Advanced; D018620:PrPSc Proteins; D020033:Protein Isoforms; C048496:N(6)-carboxymethyllysine; D014446:Tyrosine 3-Monooxygenase; D019286:Endopeptidase K; D008239:Lysine
keywords: 263K; Advanced glycation end products; Nε-(carboxymethyl)lysine; Prion disease; Prions