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Disruption of quality control system of protein/organella and Parkinson's diseases

開催日 2014/9/13
時間 17:10 - 19:10
会場 Room E(301)
Chairperson(s) 今居 譲 / Yuzuru Imai (順天堂大学大学院医学研究科 / Department of Research for Parkinson's Disease, Juntendo University Graduate School of Medicine, Japan)
長谷川 隆文 / Takafumi Hasegawa (東北大学大学院医学系研究科 / Division of Neurology, Department of Neuroscience & Sensory Organs, Tohoku University Graduate School of Medicine, Japan)

Multiple Roles of Ser129-Phosphorylation in Physiological and Pathological Functions of α-Synuclein

  • S3-E-3-2
  • 荒若 繁樹 / Shigeki Arawaka:1 佐藤 裕康 / Hiroyasu Sato:1 加藤 丈夫 / Takeo Kato:1 
  • 1:山形大・医・第3内科 / Dept Neurol, Yamagata Univ, Faculty of Med, Yamagata, Japan 

Most of &alpha-synuclein deposited as Lewy bodies, a hallmark of Parkinson's disease (PD), is phosphorylated at Ser129. Ser129-phosphorylation is a sensitive and specific marker for detecting abnormal aggregation of &alpha-synuclein in human tissues and experimental models of PD. However, it remains unclear whether or not this modification has a role in the biogenesis of Lewy bodies and neurodegeneration of PD. To find a clue for this issue, we assessed the impact of Ser129-phosphorylation on the functions of &alpha-synuclein. First, we investigated the effect of this Ser129-phosphorylation on dopamine uptake in dopaminergic SH-SY5Y cells. Our data showed that membrane-associated &alpha-synuclein enhanced dopamine uptake capacity of dopamine transporter by G-protein-coupled receptor kinases (GRKs)-mediated Ser129-phosphorylation, whereas the phosphorylation by casein kinase 2 had no effect. This suggests that &alpha-synuclein modulates intracellular dopamine levels with no functional redundancy in Ser129-phosphorylation between these kinases. Then, we investigated the metabolic fate of Ser129-phosphorylated &alpha-synuclein in SH-SY5Y cells. Experiments using cycloheximide showed that Ser129-phosphorylated &alpha-synuclein diminished rapidly, in contrast to the stable expression of total &alpha-synuclein. The short half-life of Ser129-phosphorylated &alpha-synuclein was blocked by proteasome inhibitor, MG132, to a greater extent than protein phosphatase 2A/1 inhibitor, okadaic acid. In rat primary cortical neurons, either MG132, lactacystin, or okadaic acid accumulated Ser129-phosphorylated α-synuclein. These data showed that Ser129-phosphorylated &alpha-synuclein is targeted to the proteasome pathway, in addition to undergoing dephosphorylation. Finally, we assessed the effect of Ser129-phosphorylation on &alpha-synuclein neurotoxicity in an AAV-based rat model. We found that GRK6-mediated authentic Ser129-phosphorylation significantly enhanced A53T mutant &alpha-synuclein-induced degeneration of dopaminergic neurons. Taken together, our data suggest that Ser129-phosphorylation is not only the useful marker for abnormal accumulation of &alpha-synuclein but also a modulator of physiological and pathological functions of the molecule.

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