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Parkinson's Disease and Related Disorders

開催日 2014/9/13
時間 11:00 - 12:00
会場 Poster / Exhibition(Event Hall B)

Dopamine-mediated oxidation of methionine 127 in alpha-synuclein causes neurotoxicity

  • P3-297
  • 中曽 一裕 / Kazuhiro Nakaso:1 田島 奈緒子 / Naoko Tajima:1 堀越 洋輔 / Yosuke Horikoshi:1 伊藤 悟 / Satoru Ito:2 松浦 達也 / Tatsuya Matsura:1 
  • 1:鳥取大学医学部統合分子医化学 / Div. Medical Biochemistry, Tottori Univ. Fac. of Med. Tottori, Japan 2:鳥取大学医学部脳神経内科 / Div. Neurology, Tottori Univ. Fac. of Med. 

Parkinson disease (PD) is a neurodegenerative disorder characterized by the selective loss of dopamine (DA) neurons. Many studies focused on the interaction between alpha-synuclein (asyn) and DA. Therefore, we investigated the interaction between DA and asyn with regard to cytotoxicity. To clarify the effect of DA on asyn in cells, we generated PC12 cells expressing asyn (wildtype, M116A, Y125D, M127A, S129A, and M116A/M127A). Overexpression of wildtype asyn in catecholaminergic PC12 cells decreased viability, while an inhibitor of tyrosine hydroxylase blocked this vulnerability, suggesting that asyn-related cytotoxicity is associated with DA. The vulnerabilities of mutant cell lines were lower than that of wildtype asyn-expressing cells. Moreover, asyn containing DA-mediated oxidized methionine (Met(O)) was detected in our cell line. Met(O) was lower in methionine mutant cells, but also in the Y125D and S129A mutants. Co-incubation of DA and the YEMPS peptide enhanced the production of H2O2, which may oxidize methionine residues and convert them to Met(O). Y125- or S129-lacking peptides did not enhance the production of H2O2. Our results suggest that M127 is the major target for oxidative modification by DA, and that Y125 and S129 may act as enhancers of this modification. These results may describe a mechanism of DA neuron-specific toxicity of asyn in the pathogenesis of PD.

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