Nonenzymatic Glycation at the N Terminus of Pathogenic Prion Protein in Transmissible Spongiform Encephalopathies

Yeong-Gon Choi; Jae-Il Kim; Yong-Chul Jeon; Seok-Joo Park; Eun-Kyoung Choi; Richard Rubenstein; Richard J. Kascsak; Richard I. Carp; Yong-Sun Kim

doi:10.1074/jbc.M400854200

Nonenzymatic Glycation at the N Terminus of Pathogenic Prion Protein in Transmissible Spongiform Encephalopathies*

^‡Ilsong Institute of Life Science and the ^¶Department of Microbiology, College of Medicine, Hallym University, 1605-4 Kwanyangdong, Dongangu, Anyang, Kyeonggi-Do 431-060, Republic of Korea and the ^§New York State Institute for Basic Research in Developmental Disabilities, Staten Island, New York 10314

↵∥ To whom correspondence should be addressed: Ilsong Institute of Life Science and Dept. of Microbiology, College of Medicine, Hallym University, 1605-4 Kwanyangdong, Dongangu, Anyang, Kyeonggi-Do 431-060, Republic of Korea. Tel.: 82-31-381-0954; Fax: 82-31-388-3427; E-mail: yskim{at}hallym.ac.kr.

Abstract

Transmissible spongiform encephalopathies (TSEs) are transmissible neurodegenerative diseases characterized by the accumulation of an abnormally folded prion protein, termed PrP^Sc, 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, PrP^C, 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 PrP^Sc 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.