| Co-Investigator(Kenkyū-buntansha) |
TAKAHASHI Ryosuke Kyoto University, Graduate School of Medicine, Professor, 大学院医学研究科, 教授 (90216771)
OKUMA Yasunobu Chiba Institute of Science, Faculty of Pharmaceutical Sciences, Professor, 薬学部, 教授 (20127939)
UEHARA Takashi Hokkaido University, Graduate School of Pharmaceutical Sciences, Associate Professor, 大学院薬学研究院, 助教授 (00261321)
KANEKO Masayuki Chiba Institute of Science, Faculty of Pharmaceutical Sciences, Assistant Professor, 薬学部, 講師 (10322827)
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| Research Abstract |
Protein-disulphide isomerase (PDI), which exists in endoplasmic reticulum (ER), and assists in the maturation and transport of unfolded secretory proteins. PDI has two domains that function as independent active sites with homology to the small, redox-active protein thioredoxin. We demonstrated that PDI was S-nitrosylated, a reaction transferring a nitric oxide (NO) group to a critical cysteine thiol to affect protein function. NO-induced S-nitrosylation of PDI inhibited its enzymatic activity, leads to the accumulation of polyubiquitinated proteins, and activates the unfolded protein response. Furthermore, we showed in brains manifesting sporadic Parkinson's or Alzheimer's disease, that PDI is S-nitrosylated. Thus, PDI prevents neurotoxicity associated with ER stress and protein misfolding, but NO blocks this protective effect in neurodegenerative disorders through the S-nitrosylation of PDI.
Upregulation of Parkin associated endothelin-receptor like receptor (Pael-R) in the ubiquitin-protein ligase Parkin deficient mice leads to death of dopaminergic neurons. The cell death in these animals was protected or aggaravated in upregulated or deficient mice of the ER chaperone ORP150 (150 kDa oxygen-regulated protein), respectively. We interbreed Pael-R-upregulated and Parkin knockout mice. In the mice, we observed ER-stress in the brain, selective cell death of catecholaminergic neurons in the substantia nigra and the locus ceruleus, and deficiency of mitochondria complex I. These data suggest a model in which ER-and dopamine-related stress are major contributors to decreased viability of dopaminergic neurons in a setting relevant to Parkinson's disease.
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