DAI Chen-ye , ZHANG Ze-ting , LIU Mai-li , LI Cong-gang . Application of NMR in the Studies of Structure and Interactions of α-Synuclein[J]. Chinese Journal of Magnetic Resonance, 2016 , 33(1) : 153 -167 . DOI: 10.11938/cjmr20160115

[1] Maroteaux L, Campanelli J T, Scheller R H. Synuclein: A neuron-specific protein localized to the nucleus and presynaptic nerve terminal[J]. J neurosci, 1988, 8(8): 2 804－2 815.

[2] Polymeropoulos M H, Lavedan C, Leroy E, et al. Mutation in the α-synuclein gene identified in families with Parkinson's disease[J]. Science, 1997, 276(5 321): 2 045－2 047.

[3] Spillantini M G, Schmidt M L, Lee V M Y, et al. α-synuclein in Lewy bodies[J]. Nature, 1997, 388(6 645): 839－840.

[4] Masliah E, Rockenstein E, Veinbergs I, et al. Dopaminergic loss and inclusion body formation in α-synuclein mice: implications for neurodegenerative disorders[J]. Science, 2000, 287(5 456): 1 265－1 269.

[5] Betarbet R, Sherer T B, Mackenzie G, et al. Chronic systemic pesticide exposure reproduces features of Parkinson's disease[J]. Nat Neurosci, 2000, 3(12): 1 301－1 306.

[6] Esler W P, Stimson E R, Jennings J M, et al. Alzheimer's disease amyloid propagation by a template-dependent dock-lock mechanism[J]. Biochemistry, 2000, 39(21): 6 288－6 295.

[7] Breydo L, Wu J W, Uversky V N. α-synuclein misfolding and Parkinson's disease[J]. BBA-Mol Basis of Dis, 2012, 1 822(2): 261－285.

[8] Wood S J, Wypych J, Steavenson S, et al. α-synuclein fibrillogenesis is nucleation-dependent implications for the pathogenesis of parkinson's disease[J]. J Biol Chem, 1999, 274(28): 19 509－19 512.

[9] Kessler J C, Rochet J C, Lansbury P T. The N-terminal repeat domain of α-synuclein inhibits b-sheet and amyloid fibril formation[J]. Biochemistry, 2002, 42(3): 672－678.

[10] Giasson B I, Murray I V J, Trojanowski J Q, et al. A hydrophobic stretch of 12 amino acid residues in the middle of α-synuclein is essential for filament assembly[J]. J Biol Chem, 2001, 276(4): 2 380－2 386.

[11] Bertoncini C W, Jung Y S, Fernandez C O, et al. Release of long-range tertiary interactions potentiates aggregation of natively unstructured α-synuclein[J]. Proc Nat Acad Sci USA, 2005, 102(5): 1 430－1 435.

[12] Weinreb P H, Zhen W, Poon A W, et al. NACP, a protein implicated in Alzheimer's disease and learning, is natively unfolded[J]. Biochemistry, 1996, 35(43): 13 709－13 715.

[13] Uversky V N, Li J, Fink A L. Evidence for a partially folded intermediate in α-synuclein fibril formation[J]. J Biol Chem, 2001, 276(14): 10 737－10 744.

[14] Hoyer W, Cherny D, Subramaniam V, et al. Impact of the acidic C-terminal region comprising amino acids 109~140 on α-synuclein aggregation in vitro[J]. Biochemistry, 2004, 43(51): 16 233－16 242.

[15] Fernández C O, Hoyer W, Zweckstetter M, et al. NMR of α-synuclein-polyamine complexes elucidates the mechanism and kinetics of induced aggregation [J]. EMBO J, 2004, 23(10): 2 039－2 046.

[16] Bussell R, Eliezer D. Residual structure and dynamics in parkinson's disease-associated mutants of α-synuclein[J]. J Biol Chem, 2001, 276(49): 45 996－46 003.

[17] Uversky V N. Intrinsically disordered proteins may escape unwanted interactions via functional misfolding[J]. BBA-Proteins Proteom, 2011, 1 814(5): 693－712.

[18] Wu K P, Weinstock D S, Narayanan C, et al. Structural reorganization of α-synuclein at low pH observed by NMR and REMD simulations[J]. J Mol Biol, 2009, 391(4): 784－796.

[19] Lee H J, Choi C, Lee S J. Membrane-bound α-synuclein has a high aggregation propensity and the ability to seed the aggregation of the cytosolic form[J]. J Biol Chem, 2002, 277(1): 671－678.

[20] Ulmer T S, Bax A, Cole N B, et al. Structure and dynamics of micelle-bound human α-synuclein[J]. J Biol Chem, 2005, 280(10): 9 595－9 603.

[21] Ulmer T S, Bax A. Comparison of structure and dynamics of micelle-bound human α-synuclein and Parkinson disease variants[J]. J Biol Chem, 2005, 280(52): 43 179－43 187.

[22] Michaelson D M, Barkai G, Barenholz Y. Asymmetry of lipid organization in cholinergic synaptic vesicle membranes[J]. Biochem J, 1983, 211(1): 155－162.

[23] Chandra S, Chen X, Rizo J, et al. A broken α-helix in folded α-synuclein[J]. J Biol Chem, 2003, 278(17): 15 313－ 15 318.

[24] Perrin R J, Woods W S, Clayton D F, et al. Interaction of human α-synuclein and Parkinson's disease variants with phospholipids structural analysis using site-directed mutagenesis[J]. J Biol Chem, 2000, 275(44): 34 393－34 398.

[25] Bisaglia M, Tessari I, Pinato L, et al. A topological model of the interaction between α-synuclein and sodium dodecyl sulfate micelles[J]. Biochemistry, 2005, 44(1): 329－339.

[26] Lokappa S B, Ulmer T S. α-synuclein populates both elongated and broken helix states on small unilamellar vesicles[J]. J Biol Chem, 2011, 286(24): 21 450－21 457.

[27] Jao C C, Hegde B G, Chen J, et al. Structure of membrane-bound α-synuclein from site-directed spin labeling and computational refinement[J]. Proc Nat Acad Sci USA, 2008, 105(50): 19 666－19 671.

[28] Ferreon A C M, Gambin Y, Lemke E A, et al. Interplay of α-synuclein binding and conformational switching probed by single-molecule fluorescence[J]. Proc Nat Acad Sci USA, 2009, 106(14): 5 645－5 650.

[29] Robotta M, Braun P, Van Rooijen B, et al. Direct evidence of coexisting horseshoe and extended helix conformations of membrane-bound α-synuclein[J]. Chem Phys Chem, 2011, 12(2): 267－269.

[30] Madine J, Doig A J, Middleton D A. A study of the regional effects of α-synuclein on the organization and stability of phospholipid bilayers[J]. Biochemistry, 2006, 45(18): 5 783－5 792.

[31] Pandey A P, Haque F, Rochet J-C, et al. α-synuclein-induced tubule formation in lipid bilayers[J]. J Phys Chem B, 2011, 115(19): 5 886－5 893.

[32] Nelson R, Eisenberg D. Recent atomic models of amyloid fibril structure[J]. Curr Opin Struc Biol, 2006, 16(2): 260－265.

[33] Serpell L C, Berriman J, Jakes R, et al. Fiber diffraction of synthetic α-synuclein filaments shows amyloid-like cross-b conformation[J]. Proc Nat Acad Sci USA, 2000, 97(9): 4 897－4 902.

[34] Sawaya M R, Sambashivan S, Nelson R, et al. Atomic structures of amyloid cross-b spines reveal varied steric zippers[J]. Nature, 2007, 447(7 143): 453－457.

[35] Madine J, Jack E, Stockley P G, et al. Structural insights into the polymorphism of amyloid-like fibrils formed by region 20~29 of amylin revealed by solid-state NMR and X-ray fiber diffraction[J]. J Am Chem Soc, 2008, 130(45): 14 990－ 15 001.

[36] Vilar M, Chou H T, Lührs T, et al. The fold of α-synuclein fibrils[J]. Proc Nat Acad Sci USA, 2008, 105(25): 8 637－ 8 642.

[37] Heise H, Hoyer W, Becker S, et al. Molecular-level secondary structure, polymorphism, and dynamics of full-length α-synuclein fibrils studied by solid-state NMR[J]. Proc Nat Acad Sci USA, 2005, 102(44): 15 871－15 876.

[38] Heise H, Celej M S, Becker S, et al. Solid-state NMR reveals structural differences between fibrils of wild-type and disease-related A53T mutant α-synuclein [J]. J Mol Biol, 2008, 380(3): 444－450.

[39] Lemkau L R, Comellas G, Kloepper K D, et al. Mutant protein A30P α-synuclein adopts wild-type fibril structure, despite slower fibrillation kinetics[J]. J Biol Chem, 2012, 287(14): 11 526－11 532.

[40] Rybicki B A, Johnson C C, Uman J, et al. Parkinson's disease mortality and the industrial use of heavy metals in Michigan[J]. Movement Disorders, 1993, 8(1): 87－92.

[41] Dexter D T, Carayon A, Javoy-Agid F, et al. Alterations in the levels of iron, ferritin and other trace metals in Parkinson's disease and other neurodegenerative diseases affecting the basal ganglia[J]. Brain, 1991, 114(4): 1 953－1 975.

[42] Hirsch E, Brandel J P, Galle P, et al. Iron and aluminum increase in the substantia nigra of patients with parkinson's disease: An X-ray microanalysis[J]. J Neurochem, 1991, 56(2): 446－451.

[43] Uversky V N, Li J, Fink A L. Metal-triggered structural transformations, aggregation, and fibrillation of human α-synuclein: A possible molecular link between parkinson′s disease and heavy metal exposure[J]. J Biol Chem, 2001, 276(47): 44 284－44 296.

[44] Ostrerova-Golts N, Petrucelli L, Hardy J, et al. The A53T α-synuclein mutation increases iron-dependent aggregation and toxicity[J]. J Neurosci, 2000, 20(16): 6 048－6 054.

[45] Paik S R, Shin H J, Lee J H. Metal-catalyzed oxidation of α-synuclein in the presence of copper (II) and hydrogen peroxide[J]. Arch Biochem Biophys, 2000, 378(2): 269－277.

[46] Paik S R, Lee J H, Kim D H, et al. Aluminum-induced structural alterations of the precursor of the non-Ab component of alzheimer's disease amyloid[J]. Arch Biochem Biophys, 1997, 344(2): 325－334.

[47] Hettiarachchi N T, Parker A, Dallas M L, et al. α-synuclein modulation of Ca²⁺ signaling in human neuroblastoma (SH-SY5Y) cells[J]. J Neurochem, 2009, 111(5): 1 192－1 201.

[48] Mosharov E V, Larsen K E, Kanter E, et al. Interplay between cytosolic dopamine, calcium, and α-synuclein causes selective death of substantia nigra neurons[J]. Neuron, 2009, 62(2): 218－229.

[49] Zhang Z, Dai C, Bai J, et al. Ca²⁺ modulating α-synuclein membrane transient interactions revealed by solution NMR spectroscopy[J]. BBA-Biomembranes, 2014, 1 838(3): 853－858.

[50] Tamamizu-Kato S, Kosaraju M G, Kato H, et al. Calcium-triggered membrane interaction of the α-synuclein acidic tail[J]. Biochemistry, 2006, 45(36): 10 947－10 956.

[51] Lowe R, Pountney D L, Jensen P H, et al. Calcium(II) selectively induces α-synuclein annular oligomers via interaction with the C-terminal domain[J]. Protein Sci, 2004, 13(12): 3 245－3 252.

[52] Nath S, Goodwin J, Engelborghs Y, et al. Raised calcium promotes α-synuclein aggregate formation[J]. Mol Cell Neurosci, 2011, 46(2): 516－526.

[53] Pountney D L, Lowe R, Quilty M, et al. Annular a-synuclein species from purified multiple system atrophy inclusions[J]. J Neurochem, 2004, 90(2): 502－512.

[54] Lee J C, Gray H B, Winkler J R. Copper(II) binding to α-synuclein, the parkinson's protein[J]. J Am Chem Soc, 2008, 130(22): 6 898－6 899.

[55] Binolfi A, Valiente-Gabioud A A, Duran R, et al. Exploring the structural details of Cu(I) binding to α-synuclein by NMR spectroscopy[J]. J Am Chem Soc, 2010, 133(2): 194－196.

[56] Sandal M, Valle F, Tessari I, et al. Conformational equilibria in monomeric α-synuclein at the single-molecule level[J]. PLoS Biol, 2008, 6(1): e6.

[57] Dudzik C G, Walter E D, Millhauser G L. Coordination features and affinity of the Cu²⁺ site in the α-synuclein protein of Parkinson’s disease[J]. Biochemistry, 2011, 50(11): 1 771－1 777.

[58] Sung Y H, Rospigliosi C, Eliezer D. NMR mapping of copper binding sites in α-synuclein[J]. BBA-Proteins Proteom, 2006, 1 764(1): 5－12.

[59] Lucas H R, Debeer S, Hong M S, et al. Evidence for copper-dioxygen reactivity during α-synuclein fibril formation[J]. J Am Chem Soc, 2010, 132(19): 6 636－6 637.

[60] Davies P, Moualla D, Brown D R. α-synuclein is a cellular ferrireductase[J]. PLoS ONE, 2011, 6(1): e15814.

[61] Kostka M, Högen T, Danzer K M, et al. Single particle characterization of iron-induced pore-forming α-synuclein oligomers[J]. J Biol Chem, 2008, 283(16): 10 992－11 003.

[62] André C, Truong T T, Robert J F, et al. Effect of metals on herbicides-α-synuclein association: A possible factor in neurodegenerative disease studied by capillary electrophoresis[J]. Electrophoresis, 2005, 26(17): 3 256－3 264.

[63] Binolfi A, Rasia R M, Bertoncini C W, et al. Interaction of α-synuclein with divalent metal ions reveals key differences: A link between structure, binding specificity and fibrillation enhancement[J]. J Am Chem Soc, 2006, 128(30): 9 893－9 901.

[64] Jin J, Li G J, Davis J, et al. Identification of novel proteins associated with both α-synuclein and DJ-1[J]. Mol Cell Proteomics, 2007, 6(5): 845－859.

[65] Uversky V N, Li J, Souillac P, et al. Biophysical properties of the synucleins and their propensities to fibrillate: Inhibition of α-synuclein assembly by b- and g-synucleins[J]. J Biol Chem, 2002, 277(14): 11 970－11 978.

[66] Israeli E, Sharon R. b-Synuclein occurs in vivo in lipid-associated oligomers and forms hetero-oligomers with a-synuclein[J]. J Neurochem, 2009, 108(2): 465－474.

[67] Shashidharan P, Kramer B C, Walker R H, et al. Immunohistochemical localization and distribution of torsinA in normal human and rat brain[J]. Brain Res, 2000, 853(2): 197－206.

[68] Mclean P J, Kawamata H, Shariff S, et al. Torsina and heat shock proteins act as molecular chaperones: Suppression of α-synuclein aggregation[J]. J Neurochem, 2002, 83(4): 846－854.

[69] Lo Bianco C, Shorter J, Xe, et al. Hsp104 antagonizes α-synuclein aggregation and reduces dopaminergic degeneration in a rat model of Parkinson disease[J]. J Clin Invest, 2008, 118(9): 3 087－3 097.

[70] Klucken J, Shin Y, Masliah E, et al. Hsp70 Reduces α-synuclein aggregation and toxicity[J]. J Biol Chem, 2004, 279(24): 25 497－25 502.

[71] Luk K C, Mills I P, Trojanowski J Q, et al. Interactions between Hsp70 and the hydrophobic core of α-synuclein inhibit fibril assembly[J]. Biochemistry, 2008, 47(47): 12 614－12 625.

[72] Morales R, Estrada L D, Diaz-Espinoza R, et al. Molecular cross talk between misfolded proteins in animal models of Alzheimer's and Prion diseases[J]. J Neurosci, 2010, 30(13): 4 528－4 535.

[73] Waxman E A, Giasson B I. Induction of intracellular tau aggregation is promoted by α-synuclein seeds and provides novel insights into the hyperphosphorylation of tau[J]. J Neurosci, 2011, 31(21): 7 604－7 618.

[74] Engelender S, Kaminsky Z, Guo X, et al. Synphilin-1 associates with α-synuclein and promotes the formation of cytosolic inclusions[J]. Nat Genet, 1999, 22(1): 110－114.

[75] Büttne S, Delay C, Franssens V, et al. Synphilin-1 enhances α-synuclein aggregation in yeast and contributes to cellular stress and cell death in a Sir2-dependent manner[J]. 2010, 5(10): e13700.

[76] Xie Y Y, Zhou C J, Zhou Z R, et al. Interaction with synphilin-1 promotes inclusion formation of α-synuclein: mechanistic insights and pathological implication[J]. FASEB J, 2010, 24(1): 196－205.

[77] Necula M, Chirita C N, Kuret J. Rapid anionic micelle-mediated α-synuclein fibrillization in vitro[J]. J Biol Chem, 2003, 278(47): 46 674－46 680.

[78] Zhu M, Fink A L. Lipid binding inhibits α-synuclein fibril formation[J]. J Biol Chem, 2003, 278(19): 16 873－16 877.

[79] Wang G F, Li C, Pielak G J. Probing the micelle-bound aggregation-prone state of α-synuclein with ¹⁹F NMR spectroscopy[J]. Chem Bio Chem, 2010, 11(14): 1 993－1 996.

[80] Ahmad M F, Ramakrishna T, Raman B, et al. Fibrillogenic and non-fibrillogenic ensembles of SDS-bound human α-synuclein[J]. J Mol Biol, 2006, 364(5): 1 061－1 072