Abstract
The 26S proteasome plays a major role in degradation of abnormal proteins within the cell. The indirect antioxidant including sulforaphane (SFN) protects cells from oxidative damage by increasing the expression of Nrf2-target genes. It has been observed that the expression of multiple subunits of the proteasome was up-regulated by indirect antioxidants through the Nrf2 pathway. In the current study, the role of SFN in amyloid β1–42 (Aβ1–42)-induced cytotoxicity has been investigated in murine neuroblastoma cells. Treatment with SFN protected cells from Aβ1–42-mediated cell death in Neuro2A and N1E 115 cells. Inhibition of proteasome activities by MG132 could abolish the protective effect of SFN against Aβ1–42. Neuro2A cells, which were stably overexpressing the catalytic subunit of the proteasome PSMB5, showed an elevated resistance toward Aβ1–42 toxicity compared to control cells. Furthermore, the in vitro assay demonstrated that the Aβ1–42 peptide is degraded by the proteasome fraction. These results suggest that proteasome-inducing indirect antioxidants may facilitate the removal of the Aβ1–42 peptide and lead to the amelioration of abnormal protein-associated etiologies.
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Barelli, H., Lebeau, A., Vizzavona, J., Delaere, P., Chevallier, N., Drouot, C., Marambaud, P., Ancolio, K., Buxbaum, J. D., Khorkova, O., Heroux, J., Sahasrabudhe, S., Martinez, J., Warter, J. M., Mohr, M., and Checler, F., Characterization of new polyclonal antibodies specific for 40 and 42 amino acid-long amyloid beta peptides: their use to examine the cell biology of presenilins and the immunohistochemistry of sporadic Alzheimer’s disease and cerebral amyloid angiopathy cases. Mol Med, 3, 695–707 (1997).
Carmichael, J., DeGraff, W. G., Gazdar, A. F., Minna, J. D., and Mitchell, J. B., Evaluation of a tetrazolium-based semiautomated colorimetric assay: assessment of chemosensitivity testing. Cancer Res, 47, 936–942 (1987).
Checler, F., da Costa, C. A., Ancolio, K., Chevallier, N., Lopez-Perez, E., and Marambaud, P., Role of the proteasome in Alzheimer’s disease. Biochim Biophys Acta, 1502, 133–138 (2000).
da Costa, C. A., Ancolio, K., and Checler, F., C-terminal maturation fragments of presenilin 1 and 2 control secretion of APP alpha and A beta by human cells and are degraded by proteasome. Mol Med, 5, 160–168 (1999).
Davies, K. J., Degradation of oxidized proteins by the 20S proteasome. Biochimie, 83, 301–310. (2001).
Devi, L., Prabhu, B. M., Galati, D. F., Avadhani, N. G., and Anandatheerthavarada, H. K., Accumulation of amyloid precursor protein in the mitochondrial import channels of human Alzheimer’s disease brain is associated with mitochondrial dysfunction. J Neurosci, 26, 9057–9068 (2006).
Eckert, A., Steiner, B., Marques, C., Leutz, S., Romig, H., Haass, C., and Muller, W. E., Elevated vulnerability to oxidative stress-induced cell death and activation of caspase-3 by the Swedish amyloid precursor protein mutation. J Neurosci Res, 64, 183–192 (2001).
Estus, S., Golde, T. E., and Younkin, S. G., Normal processing of the Alzheimer’s disease amyloid beta protein precursor generates potentially amyloidogenic carboxyl-terminal derivatives. Ann N Y Acad Sci, 674, 138–148 (1992).
Fahey, J. W. and Talalay, P., Antioxidant functions of sulforaphane: a potent inducer of Phase II detoxication enzymes. Food Chem Toxicol, 37, 973–979 (1999).
Glickman, M. H. and Ciechanover, A., The ubiquitin-proteasome proteolytic pathway: destruction for the sake of construction. Physiol Rev, 82, 373–428. (2002).
Gregori, L., Fuchs, C., Figueiredo-Pereira, M. E., Van Nostrand, W. E., and Goldgaber, D., Amyloid beta-protein inhibits ubiquitin-dependent protein degradation in vitro. J Biol Chem, 270, 19702–19708 (1995).
Halliwell, B., Hypothesis: proteasomal dysfunction: a primary event in neurogeneration that leads to nitrative and oxidative stress and subsequent cell death. Ann N Y Acad Sci, 962, 182–194. (2002).
Hyun, D. H., Lee, M., Halliwell, B., and Jenner, P., Proteasomal inhibition causes the formation of protein aggregates containing a wide range of proteins, including nitrated proteins. J Neurochem, 86, 363–373. (2003).
Jarrett, J. T., Berger, E. P., and Lansbury, P. T. Jr., The carboxy terminus of the beta amyloid protein is critical for the seeding of amyloid formation: implications for the pathogenesis of Alzheimer’s disease. Biochemistry, 32, 4693–4697 (1993).
Kang, J., Lemaire, H. G., Unterbeck, A., Salbaum, J. M., Masters, C. L., Grzeschik, K. H., Multhaup, G., Beyreuther, K., and Muller-Hill, B., The precursor of Alzheimer’s disease amyloid A4 protein resembles a cell-surface receptor. Nature, 325, 733–736 (1987).
Keller, J. N., Dimayuga, E., Chen, Q., Thorpe, J., Gee, J., and Ding, Q., Autophagy, proteasomes, lipofuscin, and oxidative stress in the aging brain. Int J Biochem Cell Biol. 36, 2376–2391. (2004).
Kensler, T. W., Wakabayashi, N., and Biswal, S., Cell Survival Responses to Environmental Stresses Via the Keap1-Nrf2-ARE Pathway. Annu Rev Pharmacol Toxicol, 47, 89–116 (2007).
Kwak, M. K., Cho, J. M., Huang, B., Shin, S., and Kensler, T. W., Role of increased expression of the proteasome in the protective effects of sulforaphane against hydrogen peroxidemediated cytotoxicity in murine neuroblastoma cells. Free Radic Biol Med, 43, 809–817 (2007a).
Kwak, M. K., Huang, B., Chang, H., Kim, J. A., and Kensler, T. W., Tissue specific increase of the catalytic subunits of the 26S proteasome by indirect antioxidant dithiolethione in mice: enhanced activity for degradation of abnormal protein. Life Sci, 80, 2411–2420 (2007b).
Kwak, M. K., Wakabayashi, N., Greenlaw, J. L., Yamamoto, M., and Kensler, T. W., Antioxidants enhance mammalian proteasome expression through the Keap1-Nrf2 signaling pathway. Mol Cell Biol, 23, 8786–8794. (2003a).
Kwak, M. K., Wakabayashi, N., Itoh, K., Motohashi, H., Yamamoto, M., and Kensler, T. W., Modulation of gene expression by cancer chemopreventive dithiolethiones through the Keap1-Nrf2 pathway. Identification of novel gene clusters for cell survival. J Biol Chem, 278, 8135–8145. (2003b).
LaFerla, F. M., Tinkle, B. T., Bieberich, C. J., Haudenschild, C. C., and Jay, G., The Alzheimer’s A beta peptide induces neurodegeneration and apoptotic cell death in transgenic mice. Nat Genet, 9, 21–30 (1995).
Lam, Y. A., Pickart, C. M., Alban, A., Landon, M., Jamieson, C., Ramage, R., Mayer, R. J., and Layfield, R., Inhibition of the ubiquitin-proteasome system in Alzheimer’s disease. Proc Natl Acad Sci U S A, 97, 9902–9906. (2000).
Marambaud, P., Lopez-Perez, E., Wilk, S., and Checler, F., Constitutive and protein kinase C-regulated secretory cleavage of Alzheimer’s beta-amyloid precursor protein: different control of early and late events by the proteasome. J Neurochem, 69, 2500–2505 (1997).
Masters, C. L., Simms, G., Weinman, N. A., Multhaup, G., McDonald, B. L., and Beyreuther, K., Amyloid plaque core protein in Alzheimer disease and Down syndrome. Proc Natl Acad Sci U S A, 82, 4245–4249 (1985).
Mattson, M. P., Cellular actions of beta-amyloid precursor protein and its soluble and fibrillogenic derivatives. Physiol Rev, 77, 1081–1132 (1997).
McLean, C. A., Cherny, R. A., Fraser, F. W., Fuller, S. J., Smith, M. J., Beyreuther, K., Bush, A. I., and Masters, C. L., Soluble pool of Abeta amyloid as a determinant of severity of neurodegeneration in Alzheimer’s disease. Ann Neurol, 46, 860–866 (1999).
Nunan, J., Shearman, M. S., Checler, F., Cappai, R., Evin, G., Beyreuther, K., Masters, C. L., and Small, D. H., The C-terminal fragment of the Alzheimer’s disease amyloid protein precursor is degraded by a proteasome-dependent mechanism distinct from gamma-secretase. Eur J Biochem, 268, 5329–5336 (2001).
Nunan, J., Williamson, N. A., Hill, A. F., Sernee, M. F., Masters, C. L., and Small, D. H., Proteasome-mediated degradation of the C-terminus of the Alzheimer’s disease beta-amyloid protein precursor: effect of C-terminal truncation on production of beta-amyloid protein. J Neurosci Res, 74, 378–385 (2003).
Poppek, D. and Grune, T., Proteasomal defense of oxidative protein modifications. Antioxid Redox Signal, 8, 173–184 (2006).
Seubert, P., Oltersdorf, T., Lee, M. G., Barbour, R., Blomquist, C., Davis, D. L., Bryant, K., Fritz, L. C., Galasko, D., Thal, L. J. et al., Secretion of beta-amyloid precursor protein cleaved at the amino terminus of the beta-amyloid peptide. Nature, 361, 260–263 (1993).
Shastry, B. S., Neurodegenerative disorders of protein aggregation. Neurochem Int 43, 1–7. (2003).
Stefani, M. and Dobson, C. M., Protein aggregation and aggregate toxicity: new insights into protein folding, misfolding diseases and biological evolution. J Mol Med, 27, 27 (2003).
Voges, D., Zwickl, P., and Baumeister, W., The 26S proteasome: a molecular machine designed for controlled proteolysis. Annu Rev Biochem., 68, 1015–1068. (1999).
Yankner, B. A., Dawes, L. R., Fisher, S., Villa-Komaroff, L., Oster-Granite, M. L., and Neve, R. L., Neurotoxicity of a fragment of the amyloid precursor associated with Alzheimer’s disease. Science, 245, 417–420 (1989).
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Park, HM., Kim, JA. & Kwak, MK. Protection against amyloid beta cytotoxicity by sulforaphane: Role of the proteasome. Arch. Pharm. Res. 32, 109–115 (2009). https://doi.org/10.1007/s12272-009-1124-2
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DOI: https://doi.org/10.1007/s12272-009-1124-2