N ε -CarboxymethylModification ofLysine Residues inPathogenic Prion Isoforms

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 individ- uals, particularly in the brain. A previous study has demonstrated that the N-terminus of the pathogenic prion isoform (PrP Sc )i s 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 e -(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 .W e 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 resi- due(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 hy- pothalamic nuclei. CML glycation does not occur in PrP C but is seen in the pathologic PrP Sc isoform. Furthermore, the modifica- tion of PrP Sc with CML may be closely involved in prion prop-