Enhanced oligomerization of the alpha-synuclein mutant by the Cu,Zn-superoxide dismutase and hydrogen peroxide system.
The alpha-synuclein is a major component of Lewy bodies that are found in the brains of patients with Parkinson's disease (PD). Also, two point mutations in this protein, A53T and A30P, are associated with rare familial forms of the disease. We investigated whether there are differences in the Cu,Zn-SOD and hydrogen peroxide system mediated-protein modification between the wild-type and mutant alpha-synucleins. When alpha-synuclein was incubated with both Cu,Zn-SOD and H2O2, then the amount of A53T mutant oligomerization increased relative to that of the wild-type protein. This process was inhibited by radical scavenger, spin-trapping agent, and copper chelator. These results suggest that the oligomerization of alpha-synuclein is mediated by the generation of the hydroxyl radical through the metal-catalyzed reaction. The dityrosine formation of the A53T mutant protein was enhanced relative to that of the wild-type protein. Antioxidant molecules, carnosine, and anserine effectively inhibited the wild-type and mutant proteins' oligomerization. Therefore, these compounds may be explored as potential therapeutic agents for PD patients. The present experiments, in part, may provide an explanation for the association between PD and the alpha-synuclein mutant.
Kang
Jung Hoon
JH
Department of Genetic Engineering, Chongju University, Chongju 360-764, Korea. jhkang@chongju.ac.kr
Kim
Kyung Sik
KS
D019943:Amino Acid Substitution; D000861:Anserine / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology; D000978:Antiparkinson Agents / Q000494:pharmacology; D001704:Biopolymers; D002336:Carnosine / Q000494:pharmacology; D002614:Chelating Agents / Q000494:pharmacology; D003062:Codon / Q000235:genetics; D003300:Copper; D004492:Edetic Acid / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000494:pharmacology; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D017665:Hydroxyl Radical / Q000737:chemistry; D007544:Isopropyl Thiogalactoside / Q000494:pharmacology; D016631:Lewy Bodies / Q000737:chemistry; D016297:Mutagenesis, Site-Directed; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000235:genetics; D018384:Oxidative Stress; D010300:Parkinson Disease / Q000188:drug therapy / Q000235:genetics*; D010664:Phenylmethylsulfonyl Fluoride / Q000494:pharmacology; D017354:Point Mutation; D012117:Resins, Synthetic; D013113:Spin Labels; D013482:Superoxide Dismutase / Q000494:pharmacology*; D000072105:Superoxide Dismutase-1; D051843:Synucleins; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000096:biosynthesis; D051844:alpha-Synuclein
D000975:Antioxidants; D000978:Antiparkinson Agents; D001704:Biopolymers; D002614:Chelating Agents; D003062:Codon; D016166:Free Radical Scavengers; D009419:Nerve Tissue Proteins; D012117:Resins, Synthetic; C497604:SNCA protein, human; C000606290:SOD1 protein, human; D013113:Spin Labels; D051843:Synucleins; D051844:alpha-Synuclein; C024997:Chelex 100; D017665:Hydroxyl Radical; D007544:Isopropyl Thiogalactoside; D014443:Tyrosine; D010664:Phenylmethylsulfonyl Fluoride; D003300:Copper; D002336:Carnosine; D004492:Edetic Acid; D006861:Hydrogen Peroxide; C007543:dityrosine; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D000861:Anserine