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Central Nervous System Agents in Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1871-5249
ISSN (Online): 1875-6166

Research Article

Computational Study on the Role of γ-Synuclein in Inhibiting the α-Synuclein Aggregation

Author(s): Airy Sanjeev and Venkata S.K. Mattaparthi*

Volume 19, Issue 1, 2019

Page: [24 - 30] Pages: 7

DOI: 10.2174/1871524918666181012160439

Price: $65

Abstract

Background: α-Synuclein (αS) is the precursor protein present in Lewy Bodies that helps in the formation of highly ordered amyloid fibrils that is associated with the occurrence of Parkinson’s disease, a neuro-degenerative disorder. Many reports have now been focused on finding the probable targets to weaken this debilitating disease. Recently γ-synuclein (γS), a presynaptic protein, was highlighted to inhibit the aggregation propensity of αS both in vivo and in vitro. However the nature, location and specificity of molecular interactions existing between the αS and γS is not known in spite of the potential importance of γS as an inhibitor of αS.

Objective: To understand the inhibition of αS aggregation by γS at the molecular level.

Methods: Umbrella sampling method was used along with molecular dynamics simulation to investigate the conformational dynamics, degree of association and molecular interaction between the monomeric units in the αS/γS hetero-dimer.

Results and Discussion: The dissociation energy barrier for αS/γS hetero-dimer was found to be higher than αS/αS homo-dimer. αS can therefore readily form a hetero-dimer by combining with γS than forming a homo-dimer. We also observed strong transient interactions involving hydrogen bonds, salt-bridges and non-bonded contacts between the monomeric units in αS/γS hetero-dimer.

Conclusion: Our findings suggest that γS may inhibit the aggregation propensity of αS.

Keywords: Lewy bodies, molecular dynamics, parkinson's disease, potential of mean force, self-assembly, homo-dimer.

Graphical Abstract
[1]
Bisaglia, M.; Mammi, S.; Bubacco, L. Structural insights on physiological functions and pathological effects of α-synuclein. FASEB J., 2009, 23, 329-340.
[2]
Jain, N.; Bhasne, K.; Hemaswasthi, M.; Mukhopadhyay, S. Structural and dynamical insights into the membrane-bound α-Synuclein. PLoS One, 2013, 8, e83752.
[3]
Uversky, V.N. A protein-chameleon: conformational plasticity of alpha-synuclein, a disordered protein involved in neurodegenerative disorders. J. Biomol. Struct. Dyn., 2003, 21, 211-234.
[4]
Yoon, J.; Park, J.; Jang, S.; Lee, K.; Shin, S. Conformational characteristics of unstructured peptides: Alpha-synuclein. J. Biomol. Struct. Dyn., 2008, 25, 505-515.
[5]
Deleersnijder, A.; Gerard, M.; Debyser, Z.; Baekelandt, V. The remarkable conformational plasticity of α-synuclein: Blessing or curse? Trends Mol. Med., 2013, 19, 368-377.
[6]
Lavedan, C. The Synuclein family. Genome Res., 1998, 8, 871-880.
[7]
Uversky, V.N.; Li, J.; Souillac, P.; Millett, I.S.; Doniach, S.; Jakes, R.; Goedert, M.; Fink, A.L. Biophysical properties of the synucleins and their propensities to fibrillate: Inhibition of α-synuclein assembly by β- and gamma-synucleins. J. Biol. Chem., 2002, 277, 11970-11978.
[8]
Snyder, H.; Mensah, K.; Hsu, C.; Hashimoto, M.; Surgucheva, I.G.; Festoff, B.; Surguchov, A.; Masliah, E.; Matouschek, A.; Wolozin, B. β-synuclein reduces proteosomal inhibition by α-synuclein but not γ-synuclein. J. Biol. Chem., 2005, 280, 7562-7569.
[9]
Rockenstein, E.; Hansen, L.A.; Mallory, M.; Trojanowski, J.Q.; Galasko, D.; Masliah, E. Altered expression of the synuclein family mRNA in Lewy body and Alzheimer’s disease. Brain Res., 2001, 914, 48-56.
[10]
Bendor, J.T.; Logan, T.P.; Edwards, R.H. The function of α-synuclein. Neuron, 2013, 79, 1044-1066.
[11]
Buchman, V.L.; Hunter, H.J.; Pinon, L.G.; Thompson, J.; Privalova, E.M.; Ninkina, N.N.; Davies, A.M. Persyn, a member of the synuclein family, influences neurofilament network integrity. J. Neurosci., 1998, 18, 9335-9341.
[12]
Angot, E.; Steiner, J.A. LemaTome, C.M.; Ekstrom, P.; Mattsson, B.; Bjorklund, A.; Brundin, P. α-Synuclein cell-to-cell transfer and seeding in grafted dopaminergic neurons in vivo. PLoS One, 2012, 7, e39465.
[13]
Hua, H.; Xu, L.; Wang, J.; Jing, J.; Luo, T.; Jiang, Y. Up-regulation of gamma-synuclein contributes to cancer cell survival under endoplasmic reticulum stress. J. Pathol., 2009, 217, 507-515.
[14]
Inaba, S.; Li, C.; Shi, Y.E.; Song, D.Q.; Jiang, J.D.; Liu, J. Synuclein gamma inhibits the mitotic checkpoint function and promotes chromosomal instability of breast cancer cells. Breast Cancer Res. Treat., 2005, 94, 25-35.
[15]
Ji, H.; Liu, Y.E.; Jia, T.; Wang, M.; Liu, J.; Xiao, G.; Joseph, B.K.; Rosen, C.; Shi, Y.E. Identification of a breast cancer-specific gene, BCSG1, by direct differential cDNA sequencing. Cancer Res., 1997, 57, 759-764.
[16]
Pan, Z.Z.; Bruening, W.; Giasson, B.I.; Lee, V.M.; Godwin, A.K. Gamma-synuclein promotes cancer cell survival and inhibits stress- and chemotherapy drug-induced apoptosis by modulating MAPK pathways. J. Biol. Chem., 2002, 277, 35050-35060.
[17]
Bruening, W.; Giasson, B.I.; Klein-Szanto, A.J.; Lee, V.M.; Trojanowski, J.Q.; Godwin, A.K. Synucleins are expressed in the majority of breast and ovarian carcinomas and in preneoplastic lesions of the ovary. Cancer, 2000, 88, 2154-2163.
[18]
Jiang, Y.; Liu, Y.E.; Goldberg, I.D.; Shi, Y.E. γ Synuclein, a novel heat-shock protein-associated chaperone, stimulates ligand-dependent estrogen receptor α signaling and mammary tumorigenesis. Cancer Res., 2004, 64, 4539-4546.
[19]
Surgucheva, I.G.; Sivak, J.M.; Fini, M.E.; Palazzo, R.E.; Surguchov, A.P. γ Synuclein, a novel heat-shock protein-associated chaperone, stimulates ligand-dependent estrogen receptor α signaling and mammary tumorigenesis. Arch. Biochem. Biophys., 2003, 410, 167-176.
[20]
Galvin, J.E.; Uryu, K.; Lee, V.M.; Trojanowski, J.Q. Axon pathology in Parkinson’s disease and Lewy body dementia hippocampus contains α-, β-, and gamma-synuclein. Proc. Natl. Acad. Sci. USA, 1999, 96, 13450-13455.
[21]
Ninkina, N.; Peters, O.; Millership, S.; Salem, H.; van der Putten, H.; Buchman, V.L. Gamma synucleinopathy: Neurodegeneration associated with overexpression of the mouse protein. Hum. Mol. Genet., 2009, 18, 1779-1794.
[22]
Nishioka, K.; Wider, C.; Vilarino-Guell, C.; Soto-Ortolaza, A.I.; Lincoln, S.J.; Kachergus, J.M.; Jasinska-Myga, B.; Ross, O.A.; Rajput, A.; Robinson, C.A.; Ferman, T.J.; Wszolek, Z.K.; Dickson, D.W.; Farrer, M.J. Association of alpha-, beta-, and gamma-Synuclein with diffuse lewy body disease. Arch. Neurol., 2010, 67, 970-975.
[23]
Clayton, D.F.; George, J.M. The Synucleins: A family of proteins involved in synaptic function, plasticity, neurodegeneration and disease. Trends Neurosci., 1998, 21, 249-254.
[24]
Ueda, K.; Fukushima, H.; Masliah, E.; Xia, Y.; Iwai, A.; Yoshimoto, M.; Otero, D.A.; Kondo, J.; Ihara, Y.; Saitoh, T. Molecular cloning of cDNA encoding anon-recognized component of amyloid in Alzheimer disease. Proc. Natl. Acad. Sci., 1993, 9, 11282-11286.
[25]
Berhanu, W.M.; Masunov, A.E. Atomistic mechanism of polyphenol amyloid aggregation inhibitors: Molecular dynamics study of Curcumin, Exifone, and Myricetin interaction with the segment of tau peptide oligomer. J. Biomol. Struct. Dyn., 2014, 33, 1399-1411.
[26]
Lamberto, C.R.; Torres-Monserrat, V.; Bertoncini, C.W.; Salvatella, X.; Zweckstetter, M.; Griesinger, C.; Fernandez, C.O. Toward the discovery of effective polycyclic inhibitors of α-synuclein amyloid assembly. J. Biol. Chem., 2011, 286, 32036-32044.
[27]
Lendel, C.; Bertoncini, C.W.; Cremades, N.; Waudby, C.A.; Vendruscolo, M.; Dobson, C.M.; Schenk, D.; Christodoulou, J.; Toth, G. On the mechanism of nonspecific inhibitors of protein aggregation: Dissecting the interactions of alpha-synuclein with congo red and lacmoid. Biochemistry, 2009, 48, 8322-8334.
[28]
Meng, X.Y.; Munishkina, L.A.; Fink, A.L.; Uversky, V.N. molecular mechanisms underlying the flavonoid-induced inhibition of α-synuclein fibrillation. Biochemistry, 2009, 48, 8206-8224.
[29]
Rao, J.N.; Dua, V.; Ulmer, T.S. Characterization of α-synuclein interactions with selected aggregation-inhibiting small molecules. Biochemistry, 2008, 47, 4651-4656.
[30]
Tofaris, G.K.; Layfield, R.; Spillantini, M.G. Alpha-synuclein metabolism and aggregation is linked to ubiquitin-independent degradation by the proteasome. FEBS Lett., 2001, 509, 22-26.
[31]
McNaught, K.S.; Jenner, P. Proteasomal function is impaired in substantia nigra in Parkinson’s disease. Neurosci. Lett., 2001, 297, 191-194.
[32]
Fan, Y.; Limprasert, P.; Murray, IV, J.; Smith, A.C.; Lee, V.M.Y.; Trojanowski, J.Q.; Sopher, B.L.; Spada, A.R.L. β-synuclein modulates α-synuclein neurotoxicity by reducing α-synuclein protein expression. Hum. Mol. Genet., 2006, 15, 3002-3011.
[33]
Hashimoto, M.; Bar-On, P.; Ho, G.; Takenouchi, T.; Rockenstein, E.; Crews, L.; Masliah, E. β-synuclein regulates Akt activity in neuronal cells. A possible mechanism for neuroprotection in Parkinson’s disease. J. Biol. Chem., 2004, 279, 23622-23629.
[34]
Hashimoto, M.; Rockenstein, E.; Mante, M.; Crews, L.; Bar-On, P.; Gage, F.H.; Marr, R.; Masliah, E. An anti-aggregation gene therapy strategy for Lewy body disease utilizing β-synuclein lentivirus in a transgenic model. Gene Ther., 2004, 11, 1713-1723.
[35]
Hashimoto, M.; Rockenstein, E.; Mante, M.; Mallory, M.; Masliah, E. β-Synuclein inhibits α-synuclein aggregation: A possible role as an anti-parkinsonian factor. Neuron, 2001, 32, 213-223.
[36]
Park, J.Y.; Lansbury, Jr, P.T. β-synuclein inhibits formation of α-synuclein protofibrils: A possible therapeutic strategy against Parkinson’s disease. Biochemistry, 2003, 42, 3696-3700.
[37]
Tsigelny, I.F.; Bar-On, P.; Sharikov, Y.; Crews, L.; Hashimoto, M.; Miller, M.A.; Keller, S.H.; Platoshyn, O.; Yuan, J.X.Y.; Mashiah, E. Dynamics of α-synuclein aggregation and inhibition of pore-like oligomer development by β-synuclein. FEBS J., 2007, 274, 1862-1877.
[38]
Rice, P.; Longden, I.; Bleasby, A. EMBOSS: The european molecular biology open software suite. Trends Genet., 2000, 16, 276-277.
[39]
Mehta, K.; Poddar, R.; Mukhopadhyay, K.; Kumar, M. Insight into interaction of γ-synuclein inhibiting α-synuclein oligomers-a possible strategy to cure parkinson’s disease. Intl. J. Adv. Biotechnol. Res., 2013, 4, 488-495.
[40]
Kirkwood, J.G. Statistical mechanics of fluid mixtures. J. Chem. Phys., 1935, 3, 300-313.
[41]
Duhovny, D.; Nussinov, R.; Wolfson, H.J. Efficient unbound docking of rigid molecules; Berlin, Heidelberg Springer-Verlag, 2002, pp. 185-200.
[42]
Andrusier, N.; Nussinov, R.; Wolfson, H.J. FireDock: Fast interaction refinement in molecular docking. Proteins, 2007, 69, 139-159.
[43]
Laskowski, R.A. PDBsum: Summaries and analyses of PDB structures. Nucleic Acids Res., 2001, 29, 221-222.
[44]
Zhang, Y. I-TASSER server for protein 3D structure prediction. BMC Bioinformatics, 2008, 9, 40.
[45]
Berman, H.M.; Westbrook, J.; Feng, Z.; Gilliland, G.; Bhat, T.N.; Weissig, H.; Shindyalov, I.N.; Bourne, P.E. The protein data bank. Nucleic Acids Res., 2000, 28, 235-242.
[46]
Case, D.A.; Darden, T.A.; Cheatham, T.E., III; Simmerling, C.L.; Wang, J.; Duke, R.E.; Luo, R.; Walker, R.C.; Zhang, W.; Merz, K.M.; Roberts, B.; Hayik, S.; Roitberg, A.; Seabra, G.; Swails, J.; Gotz, A.W.; Kolossvary, I.; Wong, K.F.; Paesani, F.; Vanicek, J.; Wolf, R.M.; Liu, J.; Wu, X.; Brozell, S.R.; Steinbrecher, T.; Gohlke, H.; Cai, Q.; Ye, X.; Wang, J.; Hsieh, M.J.; Cui, G.; Roe, D.R.; Mathews, D.H.; Seetin, M.G.; Salomon-Ferrer, R.; Sagui, C.; Babin, V.; Luchko, T.; Gusarov, S.; Kovalenko, A.; Kollman, P.A. AMBER 12, University of California, San Francisco 2012.
[47]
Hornak, V.; Abel, R.; Okur, A.; Strockbine, B.; Roitberg, A.; Simmerling, C. Comparison of multiple Amber force fields and development of improved protein backbone parameters. Proteins, 2006, 65, 712-725.
[48]
Sanjeev, A.; Mattaparthi, V.S.K. Effect of C-terminal truncations on the aggregation propensity of αlpha-synuclein - a potential of mean force study. J. Mol. Imaging Dyn., 2017, 7, 1-7.
[49]
Zhang, C.; Vasmatzis, G.; Cornette, J.L.; DeLisi, C. Determination of atomic desolvation energies from the structures of crystallized proteins. J. Mol. Biol., 1997, 267, 707-726.
[50]
Grossfield, A. Multidimensional free-energy calculations using the weighted histogram analysis method. J. Comput. Chem., 1995, 16, 1339-1350.
[51]
Kumar, S.; Bouzida, D.; Swendsen, R.H.; Kollmanand, P.A.; Rosenberg, J.M. The weighted histogram analysis method for free-energy calculations on biomolecules. I. the method. J. Comput. Chem., 1992, 13, 1011-1021.
[52]
Souaille, M.; Roux, B. Extension to the weighted histogram analysis method: Combining umbrella sampling with free energy calculations. Comput. Phys. Commun., 2001, 135, 40-57.
[53]
Torrie, G.M.; Valleau, J.P. Modeling condensed phase reaction dynamics. Chem. Phys. Lett., 1974, 28, 578-581.
[54]
Sanjeev, A.; Sahu, R.K.; Mattaparthi, V.S.K. Potential of mean force and molecular dynamics study on the transient interactions between α and β synuclein that drive inhibition of α-synuclein aggregation. J. Biomol. Struct. Dyn., 2016, 1-12.

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