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演題詳細

Symposium

蛋白質・オルガネラ品質管理病としてのパーキンソン病
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)

若年性パーキンソン病原因遺伝子産物によるミトコンドリア品質管理のメカニズム
Mitochondrial quality control by the gene products of early-onset Parkinson's disease

  • S3-E-3-3
  • 今居 譲 / Yuzuru Imai:1 
  • 1:順天堂大院・医 / Dept Med, Juntendo Univ , Tokyo, Japan 

Two genes linked to early onset Parkinson's disease, PINK1 and Parkin, encode a protein kinase and a ubiquitin-ligase, respectively. Both enzymes have been suggested to support mitochondrial quality control. We have reported that Parkin is phosphorylated at Ser65 within the ubiquitin-like domain by PINK1 in mammalian cultured cells. However, it remains unclear whether Parkin phosphorylation is involved in mitochondrial maintenance and activity of dopaminergic neurons in vivo. Here, we examined the effects of Parkin phosphorylation in Drosophila, in which the phosphorylation residue is conserved at Ser94. Morphological changes of mitochondria caused by the ectopic expression of wild-type Parkin in muscle tissue and brain dopaminergic neurons disappeared in the absence of PINK1. In contrast, phosphomimetic Parkin accelerated mitochondrial fragmentation or aggregation and the degradation of mitochondrial proteins regardless of PINK1 activity, suggesting that the phosphorylation of Parkin boosts its ubiquitin-ligase activity. A non-phosphorylated form of Parkin fully rescued the muscular mitochondrial degeneration due to the loss of PINK1 activity, whereas the introduction of the non-phosphorylated Parkin mutant in Parkin-null flies led to the emergence of abnormally fused mitochondria in the muscle tissue. Manipulating the Parkin phosphorylation status affected spontaneous dopamine release in the nerve terminals of dopaminergic neurons, the survivability of dopaminergic neurons and flight activity. Our data reveal that Parkin phosphorylation regulates not only mitochondrial function but also the neuronal activity of dopaminergic neurons in vivo, suggesting that the appropriate regulation of Parkin phosphorylation is important for muscular and dopaminergic functions.

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