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http://dx.doi.org/10.14348/molcells.2014.2314

Tat-Fused Recombinant Human SAG Prevents Dopaminergic Neurodegeneration in a MPTP-Induced Parkinson's Disease Model  

Sohn, Eun Jeong (Department of Biomedical Science and Research Institute of Bioscience and Biotechnology, Hallym University)
Shin, Min Jea (Department of Biomedical Science and Research Institute of Bioscience and Biotechnology, Hallym University)
Kim, Dae Won (Department of Biochemistry and Molecular Biology, Research Institute of Oral Sciences, College of Dentistry, Kangnung-Wonju National University)
Ahn, Eun Hee (Department of Biomedical Science and Research Institute of Bioscience and Biotechnology, Hallym University)
Jo, Hyo Sang (Department of Biomedical Science and Research Institute of Bioscience and Biotechnology, Hallym University)
Kim, Duk-Soo (Department of Anatomy, College of Medicine, Soonchunhyang University)
Cho, Sung-Woo (Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine)
Han, Kyu Hyung (Department of Biomedical Science and Research Institute of Bioscience and Biotechnology, Hallym University)
Park, Jinseu (Department of Biomedical Science and Research Institute of Bioscience and Biotechnology, Hallym University)
Eum, Won Sik (Department of Biomedical Science and Research Institute of Bioscience and Biotechnology, Hallym University)
Hwang, Hyun Sook (Department of Biomedical Science and Research Institute of Bioscience and Biotechnology, Hallym University)
Choi, Soo Young (Department of Biomedical Science and Research Institute of Bioscience and Biotechnology, Hallym University)
Publication Information
Molecules and Cells / v.37, no.3, 2014 , pp. 226-233 More about this Journal
Abstract
Excessive reactive oxygen species (ROS) generated from abnormal cellular process lead to various human diseases such as inflammation, ischemia, and Parkinson's disease (PD). Sensitive to apoptosis gene (SAG), a RING-FINGER protein, has anti-apoptotic activity and anti-oxidant activity. In this study, we investigate whether Tat-SAG, fused with a Tat domain, could protect SH-SY5Y neuroblastoma cells against 1-methyl-4-phenylpyridinium ($MPP^+$) and dopaminergic (DA) neurons in the substantia nigra (SN) against 1-methyl-4-phenyl-1,2,3,6-tetra-hydropyridine (MPTP) toxicity. Western blot and immunohistochemical analysis showed that, unlike SAG, Tat-SAG transduced efficiently into SH-SY5Y cells and into the brain, respectively. Tat-SAG remarkably suppressed ROS generation, DNA damage, and the progression of apoptosis, caused by $MPP^+$ in SH-SY5Y cells. Also, immunohistochemical data using a tyrosine hydroxylase antibody and cresyl violet staining demonstrated that Tat-SAG obviously protected DA neurons in the SN against MPTP toxicity in a PD mouse model. Tat-SAG-treated mice showed significant enhanced motor activities, compared to SAG- or Tat-treated mice. Therefore, our results suggest that Tat-SAG has potential as a therapeutic agent against ROS-related diseases such as PD.
Keywords
dopaminergic neuron; Parkinson's disease; protein transduction domain; reactive oxygen species; sensitive to apoptosis gene;
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1 Chanalaris, A., Sun, Y., Latchman, D.S., and Stephanou, A. (2003). SAG attenuates apoptotic cell death caused by simulated ischaemia/reoxygenation in rat cardiomyocytes. J. Mol. Cell. Cardiol. 35, 257-264.   DOI   ScienceOn
2 Ahn, E.H., Kim, D.W., Kang, H.W., Shin, M.J., Won, M.H., Kim, J., Kim, D.J., Kwon, O.S., Kang, T.C., Han, K.H., et al. (2010). Transduced PEP-1-ribosomal protein S3 (rpS3) ameliorates 12-Otetradecanoylphorbol-13-acetate-induced inflammation in mice. Toxicology 276, 192-197.   DOI   ScienceOn
3 Bae, Y.S., Oh, H., Rhee, S.G., and Yoo, Y.D. (2011). Regulation of reactive oxygen species generation in cell signaling. Mol. Cells 32, 491-509.   DOI   ScienceOn
4 Chinta, S.J., and Andersen, J.K. (2008). Redox imbalance in Parkinson's disease. Biochim. Biophys. Acta 1780, 1362-1367.
5 Dawson, T.M., and Dawson, V.L. (2003). Molecular pathways of neurodegeneration in Parkinson's disease. Science 302, 819-822.   DOI   ScienceOn
6 Duan, H., Wang, Y., Aviram, M., Swaroop, M., Loo, J.A., Bian, J., Tian, Y., Mueller, T., Bisgaier, C.L., and Sun, Y. (1999). SAG, a novel zinc RING finger protein that protects cells from apoptosis induced by redox agents. Mol. Cell. Biol. 19, 3145-3155.   DOI
7 Duan, H., Tsvetkov, L.M., Liu, Y., Song, Y., Swaroop, M., Wen, R., Kung, H.F., Zhang, H., and Sun, Y. (2001). Promotion of Sphase entry and cell growth under serum starvation by SAG/ ROC2/Rbx2/Hrt2, an E3 ubiquitin ligase component: association with inhibition of p27 accumulation. Mol. Carcinog. 30, 37-46.   DOI
8 Jeong, H.J., Kim, D.W., Woo, S.J., Kim, H.R., Kim, S.M., Jo, H.S., Park, M., Kim, D.S., Kwon, O.S., Hwang, I.K., et al. (2012). Transduced Tat-DJ-1 protein protects against oxidative stressinduced SH-SY5Y cell death and Parkinson disease in a mouse model. Mol. Cells 33, 471-478.   DOI   ScienceOn
9 Gu, Q., Tan, M., and Sun, Y. (2007). SAG/ROC2/Rbx2 is a novel activator protein-1 target that promotes c-Jun degradation and inhibits 12-O-tetradecanoylphorbol-13-acetate-induced neoplastic transformation. Cancer Res. 67, 3616-3625.   DOI   ScienceOn
10 He, H., Gu, Q., Zheng, M., Normolle, D., and Sun, Y. (2008). SAG/ROC2/RBX2 E3 ligase promotes UVB-induced skin hyperplasia, but not skin tumors, by simultaneously targeting c-Jun/AP-1 and p27. Carcinogenesis 29, 858-865.   DOI   ScienceOn
11 Huang, Y., Duan, H., and Sun, Y. (2001). Elevated expression of SAG/ROC2/Rbx2/Hrt2 in human colon carcinomas: SAG does not induce neoplastic transformation, but antisense SAG transfection inhibits tumor cell growth. Mol. Carcinog. 30, 62-70.   DOI
12 Jia, L., Yang, J., Hao, X., Zheng, M., He, H., Xiong, X., Xu, L., and Sun, Y. (2010). Validation of SAG/RBX2/ROC2 E3 ubiquitin ligase as an anticancer and radiosensitizing target. Clin. Cancer Res. 16, 814-824.   DOI
13 Kim, S.Y., Kim, M.Y., Mo, J.S., Park, J.W., and Park, H.S. (2007). SAG protects human neuroblastoma SH-SY5Y cells against 1-methyl-4-phenylpyridinium ion (MPP+)-induced cytotoxicity via the downregulation of ROS generation and JNK signaling. Neurosci. Lett. 413, 132-136.   DOI   ScienceOn
14 Kim, D.S., Kim, J.E., Kwak, S.E., Choi, K.C., Kim, D.W., Kwon, O.S., Choi, S.Y., and Kang, T.C. (2008). Spatiotemporal characteristics of astroglial death in the rat hippocampo-entorhinal complex following pilocarpine-induced status epilepticus. J. Comp. Neurol. 511, 581-598.   DOI   ScienceOn
15 Kim, D.S., Sohn, E.J., Kim, D.W., Kim, Y.N., Eom, S.A., Yoon, G.H., Cho, S.W., Lee, S.H., Hwang, H.S., Cho, Y.S., et al. (2012). PEP-1-p18 prevents neuronal cell death by inhibiting oxidative stress and Bax expression. BMB Rep. 45, 532-537.   DOI   ScienceOn
16 Lee, S.H., Kim, D.W., Eom, S.A., Jun, S.Y., Park, M., Kim, D.S., Kwon, H.J., Kwon, H.Y., Han, K.H., Park, J., et al. (2012). Suppression of 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced skin inflammation in mice by transduced Tat-Annexin protein. BMB Rep. 45, 354-359.   DOI   ScienceOn
17 Kim, D.W., Lee, S.H., Jeong, M.S., Sohn, E.J., Kim, M.J., Jeong, H.J., An, J.J., Jang, S.H., Won, M.H., Hwang, I.K., et al. (2010). Transduced Tat-SAG fusion protein protects against oxidative stress and brain ischemic insult. Free Radic. Biol. Med. 48, 969-977.   DOI   ScienceOn
18 Kim, S.Y., Yang, E.S., Lee, Y.S., Lee, J., and Park, J.W. (2011). Sensitive to apoptosis gene protein regulates ionizing radiationinduced apoptosis. Biochimie 93, 269-276.   DOI   ScienceOn
19 Miller, R.L., James-Kracke, M., Sun, G.Y., and Sun, A.Y. (2009). Oxidative and inflammatory pathways in Parkinson's disease. Neurochem. Res. 34, 55-65.   DOI   ScienceOn
20 Ramalingam, M., and Kim, S.J. (2012). Reactive oxygen/nitrogen species and their functional correlations in neurodegenerative diseases. J. Neural. Transm. 119, 891-910.   DOI   ScienceOn
21 Swaroop, M., Bian, J., Aviram, M., Duan, H., Bisgaier, C.L., Loo, J.A., and Sun, Y. (1999). Expression, purification, and biochemical characterization of SAG, a ring finger redox-sensitive protein. Free Radic. Biol. Med. 27, 193-202.   DOI   ScienceOn
22 Wei, D., and Sun, Y. (2010). Small RING finger proteins RBX1 and RBX2 of SCF E3 ubiquitin ligases: the role in cancer and as cancer targets. Genes Cancer 1, 700-707.   DOI   ScienceOn
23 Yang, G.Y., Pang, L., Ge, H.L., Tan, M., Ye, W., Liu, X.H., Huang, F.P., Wu, D.C., Che, X.M., Song, Y., et al. (2001). Attenuation of ischemia-induced mouse brain injury by SAG, a redox-inducible antioxidant protein. J. Cereb. Blood Flow Metab. 21, 722-733.   DOI
24 Tan, M., Gallegos, J.R., Gu, Q., Huang, Y., Li, J., Jin, Y., Lu, H., and Sun, Y. (2006a). SAG/ROC-SCF beta-TrCP E3 ubiquitin ligase promotes pro-caspase-3 degradation as a mechanism of apoptosis protection. Neoplasia 8, 1042-1054.   DOI
25 Tan, M., Zhu, Y., Kovacev, J., Zhao, Y., Pan, Z.Q., Spitz, D.R., and Sun, Y. (2006b). Disruption of Sag/Rbx2/Roc2 induces radiosensitization by increasing ROS levels and blocking NFkappaB activation in mouse embryonic stem cells. Free Radic. Biol. Med. 49, 976-983.
26 van den Berg, A., and Dowdym, S.F. (2011). Protein transduction domain delivery of therapeutic macromolecules. Curr. Opin. Biotechnol. 22, 888-893.   DOI   ScienceOn
27 Yang, E.S., Huh, Y.J., and Park, J.W. (2010). Knockdown of sensitive to apoptosis gene by small interfering RNA enhances the sensitivity of PC3 cells toward actinomycin D and etoposide. Free Radic. Res. 44, 864-870.   DOI   ScienceOn
28 Yoo, D.Y., Shin, B.N., Kim, I.H., Kim, D.W., Yoo, K.Y., Kim, W., Lee, C.H., Choi, J.H., Yoon, Y.S., Choi, S.Y., et al. (2012). Effects of sensitive to apoptosis gene protein on cell proliferation, neuroblast differentiation, and oxidative stress in the mouse dentate gyrus. Neurochem. Res. 37, 495-502.   DOI
29 Zhu, X., Raina, A.K., Lee, H.G., Casadesus, G., Smith, M.A., and Perry, G. (2004). Oxidative stress signalling in Alzheimer's disease. Brain Res. 1000, 32-39.   DOI   ScienceOn
30 Schwarze, S.R., Ho, A., Vocero-Akbani, A., and Dowdy, S.F. (1999). In vivo protein transduction: delivery of a biologically active protein into the mouse. Science 285, 1569-1572.   DOI   ScienceOn