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21세기 첨단과학의 꽃 Life Science
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Cell Biology Lab
Professor : Kwon-Yul Ryu
Tel : +82-2-6490-5628
Location : Natural Science Building Room 8-308
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  • Pathogenesis of neurodegenerative diseases, such as Alzheimer’s and Huntington’s diseases, is linked to the accumulation of non-native protein aggregates or inclusion bodies, which are pathological hallmarks of these disorders. In addition, abnormal accumulation of ubiquitin (Ub) within neuronal inclusion bodies has been diagnostic features of nearly all neurodegenerative diseases. Although it is clear that these diseases are associated with the accumulation of ubiquitinated aggregates, it has not been extensively studied how it leads to neuronal loss or dysfunction. Our working hypothesis is that the formation of ubiquitinated aggregates disrupts Ub pool dynamics by shifting the Ub pool equilibrium towards Ub conjugates and reducing the availability of free Ub, which is associated with diverse neurological disorders.



    Using mice as a model system, our lab is interested in identifying the role of Ubin regulating neuronal function and survival to develop Ub as a therapeutic target for neurological disorders. Ub mediates a myriad of essential signaling functions and, most importantly, plays a role in directing protein turnover by the 26S proteasome. We have directly tested the hypothesis that Ub plays an important role for neuronal function and survival by demonstrating that modest depletion of cellular Ub is sufficient to cause hypothalamic neurodegeneration and adult-onset obesity in mice by targeted disruption of one of polyubiquitin genes, Ubb.


    Current research focus includes:
    - Determine the temporal and spatial profiles of polyubiquitin gene (Ubb and Ubc) expression and regulation patterns and their contribution to total Ub levels in mouse brain under normal and stressed conditions.



    We are particularly interested how up-regulation of polyubiquitin gene expression under stressed conditions is associated with the activation of downstream molecular target.

    - Determine whether free Ub levels are reduced and Ub pool dynamics are disrupted in the affected brain regions from mouse models of neurodegeneration including Ubb knockout. Next, we will rescue neuropathological lesions by providing extra free Ub via viral-mediated delivery and/or crossing to neuron-specific Ub transgenic mice.


    - Determine the cell autonomous role of Ub in hypothalamic neuron by generating hypothalamic neuronal culture from Ubb knockout embryos and comparing their characteristics to those from wild-type embryos. This will eventually identify underlying molecular mechanisms why Ub deficiency in hypothalamic neurons causes neuronal loss or dysfunction with disruption in energy homeostasis, leading to metabolic syndrome such as obesity.


  • Recent Publications
    Kim MN, Choi J, Ryu HW, Ryu KY. (2015) Disruption of polyubiquitin gene Ubc leads to attenuated resistance against arsenite-induced toxicity in mouse embryonic fibroblasts. Biochim Biophys Acta – Mol Cell Res, 1853: 996-1009.

    Imai Y, Shiba-Fukushima K, Arano T, Matsumoto G, Inoshita T, Yoshida S, Ishihama Y, Ryu KY, Nukina N, Hattori N. (2014) Phosphorylation of mitochondrial polyubiquitin by PINK1 promotes parkin mitochondrial tethering. PLoS Genet, 10: e1004861.

    Ryu HW, Park CW, Ryu KY. (2014) Disruption of polyubiquitin gene Ubb causes dysregulation of neural stem cell differentiation with premature gliogenesis. Sci Rep, 4: 7026.

    Ryu HW, Park CW, Ryu KY. (2014) Restoration of cellular ubiquitin reverses impairments in neuronal development caused by disruption of the polyubiquitin gene Ubb. Biochem Biophys Res Commun, 453: 443–448.

    Park CW, Ryu KY. (2014) Cellular ubiquitin pool dynamics and homeostasis. BMB Rep, 47: 475–482.

    Park H, Yoon MS, Ryu KY. (2013) Disruption of polyubiquitin gene Ubc leads to defective proliferation of hepatocytes and bipotent fetal liver epithelial progenitor cells. Biochem Biophys Res Commun, 435: 434-440.

    Ryu KY*, H Park*, Rossi DJ, Weissman IL, Kopito RR. (2012) Perturbation of the hematopoietic system during embryonic liver development due to disruption of polyubiquitin gene Ubc in mice. PLoS ONE, 7: e32956. (*These two authors have equal contributions to this paper.)

    Park CW, Ryu HW, Ryu KY. (2012) Locus coeruleus neurons are resistant to dysfunction and degeneration by maintaining free ubiquitin levels although total ubiquitin levels decrease upon disruption of polyubiquitin gene Ubb. Biochem Biophys Res Commun, 418: 541-546.

    Sinnar SA, Small CL, Evanoff RM, Reinholdt LG, Griswold MD, Kopito RR, Ryu KY. (2011) Altered testicular gene expression patterns in mice lacking the polyubiquitin gene Ubb. Mol Reprod Dev, 78: 415-425.

    Ryu HW, Ryu KY. (2011) Quantification of oxidative stress in live mouse embryonic fibroblasts by monitoring the responses of polyubiquitin genes. Biochem Biophys Res Commun, 404: 470-475.

    Riley BE, Kaiser SE, Shaler TA, Ng AC, Hara T, Hipp MS, Lage K, Xavier RJ, Ryu KY, Taguchi K, Yamamoto M, Tanaka K, Mizushima N, Komatsu M, Kopito RR. (2010) Ubiquitin accumulation in autophagy-deficient mice is dependent on the Nrf2-mediated stress response pathway: a potential role for protein aggregation in autophagic substrate selection. J Cell Biol, 191: 537-552.

    Ryu KY, Fujiki N, Kazantzis M, Garza JC, Bouley DM, Stahl A, Lu XY, Nishino S, Kopito RR. (2010) Loss of polyubiquitin gene Ubb leads to metabolic and sleep abnormalities in mice. Neuropathol App Neurobiol, 36: 285-299.

    Bett JS, Benn CL, RyuKY, Kopito RR, Bates GP. (2009) The polyubiquitin Ubc gene modulates histone H2A monoubiquitylation in the R6/2 mouse models of Huntington’s disease. J Cell Mol Med, 13: 2645-2657.

    Ryu KY, Garza JC, Lu XY, Barsh GS, Kopito RR. (2008) Hypothalamic neurodegeneration and adult-onset obesity in mice lacking the Ubb polyubiquitin gene. Proc Natl Acad Sci USA, 105: 4016-4021.

    Ryu KY, Sinnar SA, Reinholdt LG, Vaccari S, Hall S, Garcia MA, Zaitseva TS, Bouley DM, Boekelheide K, Handel MA, Conti M, Kopito RR. (2008) The mouse polyubiquitin gene Ubb is essential for meiotic progression. Mol Cell Biol, 28: 1136-1146.

    Bennett EJ, Shaler TA, Woodman B, RyuKY, Zaitseva TS, Becker CH, Bates GP, Schulman H, Kopito RR. (2007) Global changes to the ubiquitin system in Huntington’s disease. Nature, 448: 704-708.

    Ryu KY, Maehr R, Gilchrist CA, Long MA, Bouley DM, Mueller B, Ploegh HL, Kopito RR. (2007) The mouse polyubiquitin gene UbC is essential for fetal liver development, cell-cycle progression and stress tolerance. EMBO J, 26: 2693-2706.

    Ryu KY, Baker RT, Kopito RR. (2006) Ubiquitin-specific protease 2 as a tool for quantification of total ubiquitin levels in biological specimens. Anal Biochem, 353: 153-155.

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