假说:TGF-β1/Smad3信号通路参与帕金森病的发生发展
A Hypothesis: TGF-β1/Smad3 Signaling Pathway Participates in the Development of Parkinson’s Disease
作者: 于永鹏 :潍坊医学院附属文登中心医院神经内科,山东 威海;
关键词: 帕金森病; 铁; 转化生长因子-β1; 6-羟基多巴胺; Parkinson’s Disease; Iron; TGF-β1; 6-Hydroxydopamine
摘要:Abstract: Parkinson’s disease (PD), which is one of neurodegenerative diseases, is a serious threat to human health. So far there has been no special treatment for it. PD onset is closely associated with the disorders of iron metabolism and its inducing and mediating oxidative stress response in the brain. The mechanism of its regulation is still elusive. Recently it was found that transforming growth factor-β1 (TGF-β1) can down-regulate the expression of ferritin heavy chain (FHC) and lead to cell labile iron increasing. It was found that TGF-β1/Smads signaling pathway could regulate cellular iron transport and metabolic balance by regulating hepcidin (Hep) expression in the hemochromatosis research. This review focused on the possible mechanism of TGF-β1/Smads signaling pathway involving iron metabolism and oxidative stress regulation and proposed a medical hypothesis: TGF-β1/Smad3 signaling pathway might participate in the process of PD de-velopment. It is expected that the experiment will be performed to explore the effect of abnormal regulation of this signaling pathway on the iron metabolism protein expressions and iron levels in PD, and to investigate regulatory mechanism of the TGF-β1 signaling on oxidative stress in dopa-minergic neurons. It will be of great significance to reveal the mechanism of PD, and to find effective treatments for it.
文章引用: 于永鹏 (2015) 假说:TGF-β1/Smad3信号通路参与帕金森病的发生发展。 自然科学, 3, 19-25. doi: 10.12677/OJNS.2015.32004
参考文献
[1] Zhang, K.H., Tian, H.Y., Gao, X., et al. (2009) Ferritin heavy chain-mediated iron homeostasis and subsequent increased reactive oxygen species production are essential for epithelial-mesenchymal transition. Cancer Research, 69, 5340-5348.
[2] Milward, E., Johnstone, D., Trinder, D., et al. (2007) The nexus of iron and inflammation in hepcidin regulation: SMADs, STATs, and ECSIT. Hepatology, 45, 253-256.
[3] Yang, W.H., Deng, Y.T., Hsieh, Y.P., Wu, K.J. and Kuo, M.Y. (2015) NADPH oxidase 4 mediates TGFβ1-induced CCN2 in gingival fibroblasts. Journal of Dental Research, pii: 0022034515580986.
[4] Oruqaj, G., Karnati, S., Vijayan, V., Kotarkonda, L.K., Boateng, E., Zhang, W., Ruppert, C., Günther, A., Shi, W, and Baumgart-Vogt, E. (2015) Compromised peroxisomes in idiopathic pulmonary fibrosis, a vicious cycle inducing a higher fibrotic response via TGF-β signaling. Proceedings of the National Academy of Sciences of the United States of America, 112, E2048-2057.
[5] Yang, Y., Kim, B., Park, Y.K., Koo, S.I. and Lee, J.Y. (2015) Astaxanthin prevents TGFβ1-induced pro-fibrogenic gene expression by inhibiting Smad3 activation in hepatic stellate cells. Biochimica et Biophysica Acta (BBA)—General Subjects, 1850, 178-185.
[6] Liu, R.M. and Gaston Pravia, K.A. (2010) Oxidative stress and glutathione in TGF-beta-mediated fibrogenesis. Free Radical Biology and Medicine, 48, 1-15.
[7] Yu, Y.P., Ju, W.P., Li, Z.G., et al. (2010) Acupuncture inhibits oxidative stress and rotational behavior in 6-hydroxydopamine lesioned rat. Brain Research, 1336, 58-65.
[8] Zecca, L., Youdim, M.B., Riederer, P., Connor, J.R. and Crichton, R.R. (2004) Iron, brain ageing and neurodegenerative disorders. Nature Reviews Neuroscience, 5, 863-873.
[9] Vila, M. and Przedborski, S. (2004) Genetic clues to the pathogenesis of Parkinson’s disease. Nature Medicine, 10, S58-S62.
[10] Wypijewska, A., Galazka-Friedman, J., Bauminger, E.R., Wszolek, Z.K., Schweitzer, K.J., Dickson, D.W., Jaklewicz, A., Elbaum, D. and Friedman, A. (2010) Iron and reactive oxygen species activity in parkinsonian substantia nigra. Parkinsonism & Related Disorders, 16, 329-333.
[11] Ke, Y. and Ming, Q.Z. (2003) Iron misregulation in the brain: A primary cause of neurodegenerative disorders. The Lancet Neurology, 2, 246-253.
[12] Song, N., Wang, J., Jiang, H. and Xie, J. (2010) Ferroportin 1 but not hephaestin contributes to iron accumulation in a cell model of Parkinson’s disease. Free Radical Biology & Medicine, 48, 332-341.
[13] Jiang, H., Song, N., Xu, H., Zhang, S., Wang, J. and Xie, J. (2010) Up-regulation of divalent metal transporter 1 in 6-hydroxydopamine intoxication is IRE/IRP dependent. Cell Research, 20, 345-356.
[14] Wang, J., Jiang, H. and Xie, J.X. (2007) Ferroportin1 and hephaestin are involved in the nigral iron accumulation of 6-OHDA-lesioned rats. European Journal of Neuroscience, 25, 2766-2772.
[15] Nagatsu, T., Mogi, M., Ichinose, H. and Togari, A. (2000) Changes in cytokines and neurotrophins in Parkinson’s disease. Journal of Neural Transmission. Supplementum, 60, 277-290.
[16] Rota, E., Bellone, G., Rocca, P., Bergamasco, B., Emanuelli, G. and Ferrero, P. (2006) Increased intrathecal TGF-beta1, but not IL-12, IFN-gamma and IL-10 levels in Alzheimer’s disease patients. Neurological Sciences, 27, 33-39.
[17] Buss, A., Pech, K., Kakulas, B.A., Martin, D., Schoenen, J., Noth, J. and Brook, G.A. (2008) TGF-beta1 and TGF- beta2 expression after traumatic human spinal cord injury. Spinal Cord, 46, 364-371.
[18] Ilzecka, J., Stelmasiak, Z. and Dobosz, B. (2002) Transforming growth factor-beta 1 (TGF-beta 1) in patients with amyotrophic lateral sclerosis. Cytokine, 20, 239-243.
[19] Krupinski, J., Kumar, P., Kumar, S. and Kaluza, J. (1996) Increased expression of TGF-beta 1 in brain tissue after ischemic stroke in humans. Stroke, 27, 852-857.
[20] Li, X., Miyajima, M., Jiang, C. and Arai, H. (2007) Expression of TGF-betas and TGF-beta type II receptor in cerebrospinal fluid of patients with idiopathic normal pressure hydrocephalus. Neuroscience Letters, 413, 141-144.
[21] Sánchez-Capelo, A., Colin, P., Guibert, B., Biguet, N.F. and Mallet, J. (2003) Transforming growth factor beta1 overexpression in the nigrostriatal system increases the dopaminergic deficit of MPTP mice. Molecular and Cellular Neuroscience, 23, 614-625.
[22] Tapia-González, S., Giráldez-Pérez, R.M., Cuartero, M.I., Casarejos, M.J., Mena, M.Á., Wang, X.F. and Sánchez- Capelo, A. (2011) Dopamine and α-synuclein dysfunction in Smad3 null mice. Molecular Neurodegeneration, 6, 72.
[23] Wang, Y. and Symes, A.J. (2010) Smad3 deficiency reduces neurogenesis in adult mice. Journal of Molecular Neuroscience, 41, 383-396.
[24] Katsuno, M., Adachi, H., Banno, H., Suzuki, K., Tanaka, F. and Sobue, G. (2011) Transforming growth factor-β signaling in motor neuron diseases. Current Molecular Medicine, 11, 48-56.
[25] Wyss-Coray, T. (2006) TGF-Beta pathway as a potential target in neurodegeneration and Alzheimer’s. Current Alzheimer Research, 3, 191-195.
[26] Caraci, F., Battaglia, G., Bruno, V., Bosco, P., Carbonaro, V., Giuffrida, M.L., Drago, F., Sortino, M.A., Nicoletti, F. and Copani, A. (2011) TGF-β1 pathway as a new target for neuroprotection in Alzheimer’s disease. CNS Neuroscience & Therapeutics, 17, 237-249.
[27] Horino, T., Ito, H., Yamaguchi, T., Furihata, M. and Hashimoto, K. (2005) Suppressive effects of iron on TGF-beta1 production by renal proximal tubular epithelial cells. Nephron Experimental Nephrology, 100, e1-e10.
[28] Lo, J. and Hurta, R.A. (2000) Transforming growth factor beta1 selectively regulates ferritin gene expression in malignant H-ras-transformed fibrosarcoma cell lines. Biochemistry and Cell Biology, 78, 527-535.
[29] Takayama, Y. and Mizumachi, K. (2010) Inhibitory effect of lactoferrin on hypertrophic differentiation of ATDC5 mouse chondroprogenitor cells. BioMetals, 23, 477-484.
[30] Rathore, K.I., Redensek, A. and David, S. (2012) Iron homeostasis in astrocytes and microglia is differentially regulated by TNF-α and TGF-β1. Glia, 60, 738-750.
[31] Zhang, H., Jiang, Z., Chang, J., Li, X., Zhu, H., Lan, H.Y., Zhou, S.F. and Yu, X. (2009) Role of NAD(P)H oxidase in transforming growth factor-beta1-induced monocyte chemoattractant protein-1 and interleukin-6 expression in rat renal tubular epithelial cells. Nephrology (Carlton), 14, 302-310.
[32] Michaeloudes, C., Sukkar, M.B., Khorasani, N.M., Bhavsar, P.K. and Chung, K.F. (2011) TGF-β regulates Nox4, MnSOD and catalase expression, and IL-6 release in airway smooth muscle cells. AJP: Lung Cellular and Molecular Physiology, 300, L295-L304.
[33] Kleinschnitz, C., Grund, H., Wingler, K., Armitage, M.E., Jones, E., Mittal, M., Barit, D., Schwarz, T., Geis, C., Kraft, P., Barthel, K., Schuhmann, M.K., Herrmann, A.M., Meuth, S.G., Stoll, G., Meurer, S., Schrewe, A., Becker, L., Gailus-Durner, V., Fuchs, H., de Klopstock, T., Angelis, M.H., Jandeleit-Dahm, K., Shah, A.M., Weissmann, N. and Schmidt, H.H. (2010) Post-stroke inhibition of induced NADPH oxidase type 4 prevents oxidative stress and neurodegeneration. PLoS Biology, 8, e1000479.