N(ɛ)-(carboxymethyl)lysine linkage to α-synuclein and involvement of advanced glycation end products in α-synuclein deposits in an MPTP-intoxicated mouse model.
This study investigated the involvement of advanced glycation end products (AGEs) that may be nonenzymatically linked to α-synuclein accumulation in the chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced C57BL/6 mouse model of parkinsonism. MPTP (20 mg/kg) was intraperitoneally administrated once daily for 30 days to the MPTP group while a saline only solution was administered to the control group. Results show that the immunoreactivities of the tyrosine hydroxylase and dopamine transporter significantly decreased in the striatum and the substantia nigra (SN) in the MPTP model compared to the subjects in the control group. α-synuclein was co-localized with N(ɛ)-(carboxymethyl)lysine (CML) and N(ɛ)-(carboxyethyl)lysine (CEL), which are well-known AGEs, in tyrosine hydroxylase-positive dopaminergic neurons in the MPTP brains. α-synuclein was also shown to be deposited in the CD11b-positive activated microglia. Some AGEs-modified proteins (CML-, CEL-, pentosidine-, or pyrraline-modified proteins) and an oligomeric form of α-synuclein appear to have almost the same molecular weight, specifically between 50 and 75 kDa; in addition, these formations were more strongly deposited in the SN region of the MPTP brains than in the control brains. Moreover, the oligomeric form of α-synuclein was modified with CML in the SNs of both the control and MPTP brains. This study, for the first time, shows that chronic dopaminergic neurodegeneration by MPTP can lead to the depositing of an oligomeric form of α-synuclein, CML-linked α-synuclein, and CEL-, pentosidine-, or pyrraline-linked proteins between 50 and 75 kDa. It is thus suggested that CML, especially a CML-linked α-synuclein oligomer between 50 and 75 kDa, may be, at least in part, involved in the aggregation of the α-synuclein induced by MPTP intoxication.
Choi
Yeong-Gon
YG
Research Team of Pain and Neuroscience, WHO Collaborating Center for Traditional Medicine, East-West Medical Research Institute, Kyung Hee University, #1 Hoegi-dong Dongdaemoon-gu, Seoul 130-701, Republic of Korea.
Lim
Sabina
S
D000818:Animals; D003342:Corpus Striatum / Q000737:chemistry; D004195:Disease Models, Animal; D050483:Dopamine Plasma Membrane Transport Proteins / Q000032:analysis; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D008239:Lysine / Q000031:analogs & derivatives* / Q000378:metabolism; D020267:MPTP Poisoning; D051379:Mice; D008810:Mice, Inbred C57BL; D010300:Parkinson Disease / Q000209:etiology / Q000473:pathology*; D013378:Substantia Nigra / Q000737:chemistry; D014446:Tyrosine 3-Monooxygenase / Q000032:analysis; D051844:alpha-Synuclein / Q000378:metabolism*
D050483:Dopamine Plasma Membrane Transport Proteins; D017127:Glycation End Products, Advanced; D051844:alpha-Synuclein; C048496:N(6)-carboxymethyllysine; D014446:Tyrosine 3-Monooxygenase; D008239:Lysine