JBPC  Vol.4 No.3 , August 2013
Dopamine cannot promote oligomerization of unoxidized α-synuclein
Abstract: α-Synuclein is the major component of the filamentous Lewy bodies and Lewy neurites that define neuropathological features of Parkinson’s disease and dementia with Lewy bodies. To investigate the oligomerization process of α-synuclein in association with dopamine (DA), the structural propensities to form oligomers were studied using NMR and other biophysical techniques. The1H-15N HSQC spectra indicated that both N- and C-termini interacted with DA. Although interactions with DA were also observed in the presence of glutathione by ESI-MS, the significant suppression of oligomerization was observed in the size exclusion chromatography, suggesting that oxidations of α-synuclein are required for its oligomerization.
Cite this paper: Shimotakahara, S. , Matsui, M. , Sakuma, C. , Takahashi, T. , Fujimoto, T. , Furihata, K. , Kojima, M. , Seino, S. , Machinami, T. , Shibusawa, Y. , Uéda, K. and Tashiro, M. (2013) Dopamine cannot promote oligomerization of unoxidized α-synuclein. Journal of Biophysical Chemistry, 4, 110-114. doi: 10.4236/jbpc.2013.43015.

[1]   Uéda, K., Fukushima, H., Masliah, E., Xia, Y., Iwai, A., Yoshimoto, M., Otero, D.A., Kondo, J., Ihara, Y. and Saitoh, T. (1993) Molecular cloning of cDNA encoding an unrecognized component of amyloid in Alzheimer disease. Proceedings of the National Academy of Sciences of USA, 90, 11282-11286. doi:10.1073/pnas.90.23.11282

[2]   Weinreb, P.H., Zhen, W., Poon, A.W., Conway, K.A. and Lansbury, P.T. (1996) NACP, a protein implicated in Alzheimer’s disease and learning, is natively unfolded. Biochemistry, 35, 13709-13715. doi:10.1021/bi961799n

[3]   Davidson, W.S., Jonas, A., Clayton, D.F. and George, J.M. (1998) Stabilization of α-synuclein secondary structure upon binding to synthetic membranes. The Journal of Biological Chemistry, 273, 9443-9449. doi:10.1074/jbc.273.16.9443

[4]   George, J.M., Jin, H., Woods, W.S. and Clayton, D.F. (1995) Characterization of a novel protein regulated during the critical period for song learning in the zebra finch. Neuron, 15, 361-372. doi:10.1016/0896-6273(95)90040-3

[5]   Iwai, A., Masliah, E., Yoshimoto, M., Ge, N., Flanagan, L., De Silva, H.A., Kittel, A. and Saitoh, T. (1995) The precursor protein of non-A beta component of Alzheimer’s disease amyloid is a presynaptic protein of the central nervous system. Neuron, 14, 467-475. doi:10.1016/0896-6273(95)90302-X

[6]   Ma, Q.L., Chan, P., Yoshii, M. and Uéda, K. (2003) Alpha-synuclein aggregation and neurodegenerative diseases. Journal of Alzheimer’s Disease, 5, 139-148.

[7]   Yu, S., Li, X., Liu, G., Han, J., Zhang, C., Li, Y., Xu, S., Liu, C., Gao, Y., Yang, H., Uéda, K. and Chan, P. (2007) Extensive nuclear localization of alpha-synuclein in normal rat brain neurons revealed by a novel monoclonal antibody. Neuroscience, 145, 539-555. doi:10.1016/j.neuroscience.2006.12.028

[8]   Conway, K.A., Rochet, J.C., Bieganski, R.M. and Lansbury, P.T. Jr. (2001) Kinetic stabilization of the alpha-synucleinprotofibril by a dopamine-alpha-synuclein adduct. Science, 294, 1346-1349. doi:10.1126/science.1063522

[9]   Pham, C.L.L., Leong, S.L., Ali, F.E., Kenche, V.B., Hill, A.F., Gras, S.L., Barnham, K.J. and Cappai, R. (2009) Dopamine and the dopamine oxidation product 5,6-dihydroxylindole promote distinct on-pathway and off-pathway aggregation of alpha-synuclein in a pH-dependent manner. Journal of Molecular Biology, 387, 771-785. doi:10.1016/j.jmb.2009.02.007

[10]   Rekas, A., Knott, R.B., Sokolova, A., Barnham, K.J., Perez, K.A., Masters, C.L., Drew, S.C., Cappai, R., Curtain, C.C. and Pham, C.L.L. (2010) The structure of dopamine induced α-synuclein oligomers. European Biophysics Journal, 39, 1407-1419. doi:10.1007/s00249-010-0595-x

[11]   Bisaglia, M., Tosatto, L., Munari, F., Tessari, I., de Laureto, P.P., Mammi, S. and Bubacco, L. (2010) Dopamine quinones interact with α-synuclein to form unstructured adducts. Biochemical and Biophysical Research Communications, 394, 424-428. doi:10.1016/j.bbrc.2010.03.044

[12]   Lee, H.J., Baek, S.M., Ho, D.H., Suk, J.E., Cho, E.D. and Lee, S.J. (2011) Dopamine promotes formation and secretion of non-fibrillar alpha-synuclein oligomers. Experimental and Molecular Medicine, 43, 216-222. doi:10.3858/emm.2011.43.4.026

[13]   Kamiyoshihara, T., Kojima, M., Uéda, K., Tashiro, M. and Shimotakahara, S. (2007) Observation of multiple intermediates in α-synuclein fibril formation by singular value decomposition analysis. Biochemical and Biophysical Research Communications, 355, 398-403. doi:10.1016/j.bbrc.2007.01.162

[14]   Tashiro, M., Kojima, M., Kihara, H., Kasai, K., Kamiyo-shihara, T., Uéda, K. and Shimotakahara, S. (2008) Characterization of fibrillation process of α-synuclein at the initial stage. Biochemical and Biophysical Research Communications, 369, 910-914. doi:10.1016/j.bbrc.2008.02.127

[15]   Shimotakahara, S., Shiroyama, Y., Fujimoto, T., Akai, M., Onoue, T., Seki, H., Kado, S., Machinami, T., Shibusawa, Y., Uéda, K. and Tashiro, M. (2012) Demonstration of three dopamine molecules bound to α-synuclein: Implication of oligomerization at the initial stage. Journal of Biophysical Chemistry, 3, 149-155. doi:10.4236/jbpc.2012.32017

[16]   Furihata, K., Shimotakahara, S. and Tashiro, M. (2008) An efficient use of the WATERGATE W5 sequence for observing a ligand binding with a protein receptor. Magnetic Resonance in Chemistry, 46, 799-802. doi:10.1002/mrc.2264

[17]   Mazzulli, J.R., Armakola, M., Dumoulin, M., Parastatidis, I. and Ischiropoulos, H. (2007) Cellular oligomerization of alpha-synuclein is determined by the interaction of oxidized catechols with a C-terminal sequence. The Journal of Biological Chemistry, 282, 31621-31630. doi:10.1074/jbc.M704737200

[18]   Leong, S.L., Cappaim, R., Barnhamm, K.J. and Pham, C.L. Modulation of alpha-synuclein aggregation by dopamine: A review. (2009) Neurochemical Research, 34, 1838-1846. doi:10.1007/s11064-009-9986-8

[19]   Leong, S.L, Pham, C.L., Galatis, D., Fodero-Tavoletti, M.T., Perez, K., Hill, A.F., Masters, C.L., Ali, F.E., Barnham, K.J. andCappai, R. (2009) Formation of dopamine- mediated alpha-synuclein-soluble oligomers requires methionine oxidation. Free Radical Biology & Medicine, 46, 1328-1337. doi:10.1016/j.freeradbiomed.2009.02.009

[20]   Surgucheva, I., Sharov, V.S., Surguchov, A, (2012) γ-Synuclein: Seeding of α-synuclein aggregation and transmission between cells. Biochemsiry, 51, 4743-4754. doi:10.1021/bi300478w