Abstract
Alpha-synuclein (α-SYN) is a small and highly conserved presynaptic protein that is implicated in both normal brain function and the pathogenesis of neurodegenerative diseases. Although the physiological function of α-SYN has not been fully evaluated, several lines of evidence suggest that it plays an important role in the regulation of dopamine homeostasis in the brain. Early studies have demonstrated that interaction of α-SYN and tyrosine hydroxylase (TH), a rate-limiting enzyme in dopamine synthesis, is functionally significant for dopaminergic neurotransmission and the pathophysiology of Parkinson’s disease. In the present study, we would like to evaluate whether overexpression of wild-type or mutant α-SYN might affect cAMP/PKA-dependent TH activation in DA-producing SK-N-BE(2)C cells. Here we show that wild-type and mutant A30P and A53T α-SYN attenuate forskolin-induced TH up-regulation, but do not suppress TH basal expression in SK-N-BE(2)C cells. Forskolin-induced increase in TH promoter activity and CRE-dependent transcription are significantly suppressed in α-SYN-overexpressing cells. Alpha-SYN enters the nucleus, but does not bind to CREB or interfere with forskolin-induced CREB phosphorylation. These data indicate that elevated levels of α-SYN due to a specific disease or the normal aging process could be associated with dopaminergic neuronal dysfunction through interference with TH regulation.
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Abeliovich, A., Schmitz, Y., Fariñas, I., Choi-Lundberg, D., Ho, W. H., Castillo, P. E., Shinsky, N., Verdugo, J. M., Armanini, M., Ryan, A., Hynes, M., Phillips, H., Sulzer, D., and Rosenthal, A., Mice lacking alpha-synuclein display functional deficits in the nigrostriatal dopamine system. Neuron, 25, 239–252 (2000).
Carlezon, W. A. Jr., Duman, R. S., and Nestler, E. J., The many faces of CREB. Trends Neurosci., 28, 436–445 (2005).
Chae, S. W., Bang, Y. J., Kim, K. M., Lee, K. Y., Kang, B. Y., Kim, E. M., Inoue, H., Hwang, O., and Choi, H. J., Role of cyclooxygenase-2 in tetrahydrobiopterin-induced dopamine oxidation. Biochem. Biophys. Res. Commun., 359, 735–741 (2007).
Chu, Y., Kompoliti, K., Cochran, E. J., Mufson, E. J., and Kordower, J. H., Age-related decreases in Nurr1 immunoreactivity in the human substantia nigra. J. Comp. Neurol., 450, 203–214 (2002).
DeMarch, Z., Giampà, C., Patassini, S., Martorana, A., Bernardi, G., and Fusco, F. R., Beneficial effects of rolipram in a quinolinic acid model of striatal excitotoxicity. Neurobiol. Dis., 25, 266–273 (2007).
Døskeland, A. P. and Flatmark, T., Recombinant human phenylalanine hydroxylase is a substrate for the ubiquitinconjugating enzyme system. Biochem. J., 319 (Pt 3), 941–945 (1996).
Dunkley, P. R., Bobrovskaya, L., Graham, M. E., von Nagy-Felsobuki, E., and Dickson, P. W., Tyrosine hydroxylase phosphorylation: regulation and consequences. J. Neurochem., 91, 1025–1043 (2004).
Emborg, M. E., Ma, S. Y., Mufson, E. J., Levey, A. I., Taylor, M. D., Brown, W. D., Holden, J. E., and Kordower, J. H., Agerelated declines in nigral neuronal function correlate with motor impairments in rhesus monkeys. J. Comp. Neurol., 401, 253–265 (1998).
Flatmark, T., Catecholamine biosynthesis and physiological regulation in neuroendocrine cells. Acta Physiol. Scand., 168, 1–17 (2000).
Goers, J., Manning-Bog, A. B., McCormack, A. L., Millett, I. S., Doniach, S., Di Monte, D. A., Uversky, V. N., and Fink, A. L., Nuclear localization of alpha-synuclein and its interaction with histones. Biochemistry, 42, 8465–8471 (2003).
Haycock, J. W., Phosphorylation of tyrosine hydroxylase in situ at serine 8, 19, 31, and 40. J. Biol. Chem., 265, 11682–11691 (1990).
Hegde, M. L., Vasudevaraju, P., and Rao, K. J., DNA induced folding/fibrillation of alpha-synuclein: new insights in Parkinson’s disease. Front Biosci., 15, 418–436 (2010).
Impey, S., McCorkle, S. R., Cha-Molstad, H., Dwyer, J. M., Yochum, G. S., Boss, J. M., McWeeney, S., Dunn, J. J., Mandel, G., and Goodman, R. H., Defining the CREB regulon: a genome-wide analysis of transcription factor regulatory regions. Cell, 119, 1041–1054 (2004).
Jakes, R., Spillantini, M. G., and Goedert, M., Identification of two distinct synucleins from human brain. FEBS Lett., 345, 27–32 (1994).
Kim, K. S., Lee, M. K., Carroll, J., and Joh, T. H., Both the basal and inducible transcription of the tyrosine hydroxylase gene are dependent upon a cAMP response element. J. Biol. Chem., 268, 15689–15695 (1993).
Kontopoulos, E., Parvin, J. D., and Feany, M. B., Alphasynuclein acts in the nucleus to inhibit histone acetylation and promote neurotoxicity. Hum. Mol. Genet., 15, 3012–3023 (2006).
Krüger, R., Kuhn, W., Müller, T., Woitalla, D., Graeber, M., Kösel, S., Przuntek, H., Epplen, J. T., Schöls, L., and Riess, O., Ala30Pro mutation in the gene encoding alphasynuclein in Parkinson’s disease. Nat. Genet., 18, 106–108(1998).
Kumer, S. C. and Vrana, K. E., Intricate regulation of tyrosine hydroxylase activity and gene expression. J. Neurochem., 67, 443–462 (1996).
Lazaroff, M., Qi, Y., and Chikaraishi, D. M., Differentiation of a catecholaminergic CNS cell line modifies tyrosine hydroxyl-ase transcriptional regulation. J. Neurochem., 71, 51–59 (1998).
Lee, F. J., Liu, F., Pristupa, Z. B., and Niznik, H. B., Direct binding and functional coupling of alpha-synuclein to the dopamine transporters accelerate dopamine-induced apoptosis. FASEB J., 15, 916–926 (2001).
Lindgren, N., Xu, Z. Q., Lindskog, M., Herrera-Marschitz, M., Goiny, M., Haycock, J., Goldstein, M., Hökfelt, T., and Fisone, G., Regulation of tyrosine hydroxylase activity and phosphorylation at Ser(19) and Ser(40) via activation of glutamate NMDA receptors in rat striatum. J. Neurochem., 74, 2470–2477 (2000).
Lotharius, J. and Brundin, P., Impaired dopamine storage resulting from alpha-synuclein mutations may contribute to the pathogenesis of Parkinson’s disease. Hum. Mol. Genet., 11, 2395–2407 (2002).
Mayr, B. and Montminy, M., Transcriptional regulation by the phosphorylation-dependent factor CREB. Nat. Rev. Mol. Cell Biol., 2, 599–609 (2001).
McNaught, K. S., Olanow, C. W., Halliwell, B., Isacson, O., and Jenner, P., Failure of the ubiquitin-proteasome system in Parkinson’s disease. Nat. Rev. Neurosci., 2, 589–594 (2001).
Melia, K. R., Rasmussen, K., Terwilliger, R. Z., Haycock, J. W., Nestler, E. J., and Duman, R. S., Coordinate regulation of the cyclic AMP system with firing rate and expression of tyrosine hydroxylase in the rat locus coeruleus: effects of chronic stress and drug treatments. J. Neurochem., 58, 494–502 (1992).
Mosharov, E. V., Staal, R. G., Bové, J., Prou, D., Hananiya, A., Markov, D., Poulsen, N., Larsen, K. E., Moore, C. M., Troyer, M. D., Edwards, R. H., Przedborski, S., and Sulzer, D., Alpha-synuclein overexpression increases cytosolic catecholamine concentration. J. Neurosci., 26, 9304–9311 (2006).
Mosharov, E. V., Larsen, K. E., Kanter, E., Phillips, K. A., Wilson, K., Schmitz, Y., Krantz, D. E., Kobayashi, K., Edwards, R. H., and Sulzer, D., Interplay between cytosolic dopamine, calcium, and alpha-synuclein causes selective death of substantia nigra neurons. Neuron, 62, 218–229 (2009).
Naoi, M. and Maruyama, W., Cell death of dopamine neurons in aging and Parkinson’s disease. Mech. Ageing Dev., 111, 175–188 (1999).
Ostrerova, N., Petrucelli, L., Farrer, M., Mehta, N., Choi, P., Hardy, J., and Wolozin, B., alpha-Synuclein shares physical and functional homology with 14-3-3 proteins. J. Neurosci., 19, 5782–5791 (1999).
Peng, X., Tehranian, R., Dietrich, P., Stefanis, L., and Perez, R. G., Alpha-synuclein activation of protein phosphatase 2A reduces tyrosine hydroxylase phosphorylation in dopaminergic cells. J. Cell Sci., 118, 3523–3530 (2005).
Perez, R. G., Waymire, J. C., Lin, E., Liu, J. J., Guo, F., and Zigmond, M. J., A role for alpha-synuclein in the regulation of dopamine biosynthesis. J. Neurosci., 22, 3090–3099 (2002).
Polymeropoulos, M. H., Lavedan, C., Leroy, E., Ide, S. E., Dehejia, A., Dutra, A., Pike, B., Root, H., Rubenstein, J., Boyer, R., Stenroos, E., Chandrasekharappa, S., Athanassiadou, A., Papapetropoulos, T., Johnson, W. G., Lazzarini, A. M., Duvoisin, R. C., Di Iorio, G., Golbe, L. I., and Nussbaum, R. L., Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease. Science, 276, 2045–2047 (1997).
Ramsey, A. J. and Fitzpatrick, P. F., Effects of phosphorylation of serine 40 of tyrosine hydroxylase on binding of catecholamines: evidence for a novel regulatory mechanism. Biochemistry, 37, 8980–8986 (1998).
Reesink, F. E., Lemstra, A. W., Van Dijk, K. D., Berendse, H. W., Van de Berg, W. D., Klein, M., Blankenstein, M. A., Scheltens, P., Verbeek, M. M., and van der Flier, W. M., CSF α-Synuclein does not discriminate dementia with lewy bodies from Alzheimer’s disease. J. Alzheimers Dis., 22, 87–95 (2010).
Spillantini, M. G., Schmidt, M. L., Lee, V. M., Trojanowski, J. Q., Jakes, R., and Goedert, M., Alpha-synuclein in Lewy bodies. Nature, 388, 839–840 (1997).
Uéda, K., Fukushima, H., Masliah, E., Xia, Y., Iwai, A., Yoshimoto, M., Otero, D. A., Kondo, J., Ihara, Y., and Saitoh, T., Molecular cloning of cDNA encoding an unrecognized component of amyloid in Alzheimer disease. Proc. Natl. Acad. Sci. U. S. A., 90, 11282–11286 (1993).
Wong, D. L. and Tank, A. W., Stress-induced catecholaminergic function: transcriptional and post-transcriptional control. Stress, 10, 121–130 (2007).
Yavich, L., Tanila, H., Vepsäläinen, S., and Jäkälä, P., Role of alpha-synuclein in presynaptic dopamine recruitment. J. Neurosci., 24, 11165–11170 (2004).
Yavich, L., Jäkälä, P., and Tanila, H., Abnormal compartmentalization of norepinephrine in mouse dentate gyrus in alpha-synuclein knockout and A30P transgenic mice. J. Neurochem., 99, 724–732 (2006).
Yu, S., Zuo, X., Li, Y., Zhang, C., Zhou, M., Zhang, Y. A., Uéda, K., and Chan, P., Inhibition of tyrosine hydroxylase expression in alpha-synuclein-transfected dopaminergic neuronal cells. Neurosci. Lett., 367, 34–39 (2004).
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Kim, S.S., Moon, K.R. & Choi, H.J. Interference of alpha-synuclein with cAMP/PKA-dependent CREB signaling for tyrosine hydroxylase gene expression in SK-N-BE(2)C cells. Arch. Pharm. Res. 34, 837–845 (2011). https://doi.org/10.1007/s12272-011-0518-0
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DOI: https://doi.org/10.1007/s12272-011-0518-0