α-Synuclein Misfolding Versus Aggregation Relevance to Parkinson’s Disease: Critical Assessment and Modeling

Molecular Neurobiology

Volumn 51, Issue 3, 2015, Pages 1417-1431

  Berrocal, Ruben ^a,b   Vasquez, Velmarini ^a,b   KRS, Sambasiva Rao ^a,b   Gadad, Bharathi S ^c   KS, Rao ^a  

^a INSTITUTO DE INVESTIGACIONES CIENTÍFICAS Y SERVICIOS DE ALTA TECNOLOGÍA   (Panama)

^b ACHARYA NAGARJUNA UNIVERSITY   (India)

^c UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER   (United States)

Author keywords

Aggregation; Conformation; Metals; Misfolding; Parkinson s disease; Synuclein

Indexed keywords

ALPHA SYNUCLEIN;

ANIMAL; HUMAN; KINETICS; METABOLISM; PARKINSON DISEASE; PHYSIOLOGY; PROTEIN CONFORMATION; PROTEIN FOLDING; PROTEIN SECONDARY STRUCTURE;

ALPHA-SYNUCLEIN; ANIMALS; HUMANS; KINETICS; PARKINSON DISEASE; PROTEIN CONFORMATION; PROTEIN FOLDING; PROTEIN STRUCTURE, SECONDARY;

EID: 84939896736     PISSN: 08937648     EISSN: 15591182     Source Type: Journal    
DOI: 10.1007/s12035-014-8818-2     Document Type: Review

References (94)

1. Polymeropoulos MH, Lavedan C, Leroy E, Ide SE, Dehejia A, Dutra A, Pike B, Root H, Rubenstein J et al (1997) Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease. Science 276:2045–2047
2. Wakabayashi K, Matsumoto K, Takayama K, Yoshimoto M, Takahashi H (1997) NACP, a presynaptic protein, immunoreactivity in Lewy bodies in Parkinson’s disease. Neurosci Lett 239:45–48
3. Spillantini MG, Schimdt ML, Lee VM, Trojanowski JQ, Jakes R, Goedert M (1997) α-Synuclein in Lewy bodies. Nature 388:839–840
4. Kruger R, Kuhn W, Muller T, Woitalla D, Graeber M, Kosel S, Przuntek H, Epplen JT, Schols L, Riess O (1998) Ala30Pro mutation in the gene encoding alpha-synuclein in Parkinson’s disease. Nat Genet 18:106–108
5. Zarranz JJ, Alegre J, Gomez-Esteban JC, Lezcano E, Ros R, Ampuero I, Vidal L, Hoenicka J, Rodriguez O, Atares B, Llorens V et al (2004) The new mutation, E46K, of alpha-synuclein causes Parkinson and Lewy body dementia, Ann. Neurol 55:164–173
6. Conway KA, Harper JD, Lansbury PT (1998) Accelerated in vitro fibril formation by a mutant alpha-synuclein linked to early-onset Parkinson disease. Nat Med 4:1318–20. doi:10.1038/3311
7. Puschmann A, Wszolek ZK, Farrer M, Gustafson L, Widner H, Nilsson C (2009) Alpha-synuclein multiplications with parkinsonism, dementia or progressive myoclonus? Parkinsonism Relat Disord 15(5):390–2
8. Biskup S, Gerlach M, Kupsch A, Reichmann H, Riederer P, Vieregge P, Wüllner U, Gasser T (2008) Genes associated with Parkinson syndrome. J Neurol 255(Suppl 5):8–17
9. Tsigelny IF, Sharikov Y, Miller MA, Masliah E (2008) Mechanism of alpha-synuclein oligomerization and membrane interaction: theoretical approach to unstructured proteins studies. Nanomedicine 4(4):350–7
10. Uversky VN, Li J, Fink AL (2001) Evidence for a partially folded intermediate in α-synuclein fibril formation. J Biol Chem 276:10737–10744
11. Uversky VN, Li J, Fink AL (2001) Metal-triggered structural transformation, aggregation and fibrillation of human α-synuclein, a possible molecular link between Parkinson’s disease and heavy metal exposure. J Biol Chem 276:44284–44296
12. Buchman VL, Adu J, Pinõn LG, Ninkina NN, Davies AM (1998) Persyn, a member of the synuclein family, influences neurofilament network integrity. Nat Neurosci 1(2):101–3
13. Heise H, Celej MS, Becker S, Riedel D, Pelah A, Kumar A, Jovin TM, Baldus M (2008) Solid-state NMR reveals structural differences between fibrils of wild-type and disease-related A53T mutant alpha-synuclein. J Mol Biol 380(3):444–50
14. Bertoncini CW, Fernandez CO, Griesinger C, Jovin TM, Zweckstetter M (2005) Familial mutants of alpha-synuclein with increased neurotoxicity have a destabilized conformation. J Biol Chem 280(35):30649–52
15. Vilar M, Chou HT, Lührs T, Maji SK, Riek-Loher D, Verel R, Manning G, Stahlberg H, Riek R (2008) The fold of alpha-synuclein fibrils. Proc Natl Acad Sci U S A 105(25):8637–42
16. Wu KP, Kim S, Fela DA, Baum J (2008) Characterization of conformational and dynamic properties of natively unfolded human and mouse alpha-synuclein ensembles by NMR: implication for aggregation. J Mol Biol 378(5):1104–15
17. Gath J, Bousset L, Habenstein B et al (2013) Yet another polymorph of α-synuclein: solid-state sequential assignments. Biomol NMR Assign. doi:10.1007/s12104-013-9526-y
18. Schwalbe M, Ozenne V, Bibow S et al (2014) Predictive atomic resolution descriptions of intrinsically disordered hTau40 and α-synuclein in solution from NMR and small angle scattering. Structure 22:238–49. doi:10.1016/j.str.2013.10.020
19. Jiang P, Ko LW, Jansen KR, Golde TE, Yen SH (2008) Using leucine zipper to facilitate alpha-synuclein assembly. FASEB J 22(9):3165–7
20. Varkey J, Isas JM, Mizuno N et al (2010) Membrane curvature induction and tubulation are common features of synucleins and apolipoproteins. J Biol Chem 285:32486–93. doi:10.1074/jbc.M110.139576
21. Wu K-P, Kim S, Fela DA, Baum J (2008) Characterization of conformational and dynamic properties of natively unfolded human and mouse alpha-synuclein ensembles by NMR: implication for aggregation. J Mol Biol 378:1104–15. doi:10.1016/j.jmb.2008.03.017
22. Recchia A, Debetto P, Negro A et al (2004) Alpha-synuclein and Parkinson’s disease. FASEB J 18:617–26. doi:10.1096/fj.03-0338rev
23. Lemkau LR, Comellas G, Lee SW et al (2013) Site-specific perturbations of alpha-synuclein fibril structure by the Parkinson’s disease associated mutations A53T and E46K. PLoS One 8:e49750. doi:10.1371/journal.pone.0049750
24. Petersen B, Petersen TN, Andersen P et al (2009) A generic method for assignment of reliability scores applied to solvent accessibility predictions. BMC Struct Biol 9:51. doi:10.1186/1472-6807-9-5
25. Miake H, Mizusawa H, Iwatsubo T, Hasegawa M (2002) Biochemical characterization of the core structure of alpha-synuclein filaments. J Biol Chem 277:19213–9. doi:10.1074/jbc.M110551200
26. Deng X, Eickholt J, Cheng J (2012) A comprehensive overview of computational protein disorder prediction methods. Mol Biosyst 8:114–21. doi:10.1039/c1mb05207a
27. McGuffin LJ (2008) Intrinsic disorder prediction from the analysis of multiple protein fold recognition models. Bioinformatics 24:1798–804. doi:10.1093/bioinformatics/btn326
28. Prilusky J, Felder CE, Zeev-Ben-Mordehai T et al (2005) FoldIndex: a simple tool to predict whether a given protein sequence is intrinsically unfolded. Bioinformatics 21:3435–8. doi:10.1093/bioinformatics/bti537
29. Zhang Y (2008) I-TASSER server for protein 3D structure prediction. BMC Bioinformatics 9:40. doi:10.1186/1471-2105-9-40
30. Roy A, Kucukural A, Zhang Y (2010) I-TASSER: a unified platform for automated protein structure and function prediction. Nat Protoc 5:725–38. doi:10.1038/nprot.2010.5
31. Buchan DW a, Minneci F, Nugent TCO, et al. (2013) Scalable web services for the PSIPRED Protein Analysis Workbench. Nucleic Acids Res 41:W349–57. doi: 10.1093/nar/gkt381
32. Hegde ML, Rao KSJ (2007) DNA induces folding in alpha-synuclein: understanding the mechanism using chaperone property of osmolytes. Arch Biochem Biophys 464:57–69. doi:10.1016/j.abb.2007.03.042
33. Qin Z, Hu D, Han S et al (2007) Role of different regions of alpha-synuclein in the assembly of fibrils. Biochemistry 46:13322–30. doi:10.1021/bi7014053
34. Murray IVJ, Giasson BI, Quinn SM et al (2003) Role of alpha-synuclein carboxy-terminus on fibril formation in vitro. Biochemistry 42:8530–40. doi:10.1021/bi027363r
35. Laskowski RA, Rullmannn JA, MacArthur MW et al (1996) AQUA and PROCHECK-NMR: programs for checking the quality of protein structures solved by NMR. J Biomol NMR 8:477–86
36. Schymkowitz J, Borg J, Stricher F et al (2005) The FoldX web server: an online force field. Nucleic Acids Res 33:W382–8. doi:10.1093/nar/gki387
37. Van Durme J, Delgado J, Stricher F et al (2011) A graphical interface for the FoldX forcefield. Bioinformatics 27:1711–2. doi:10.1093/bioinformatics/btr254
38. Guerois R, Nielsen JE, Serrano L (2002) Predicting changes in the stability of proteins and protein complexes: a study of more than 1000 mutations. J Mol Biol 320:369–87. doi:10.1016/S0022-2836(02)00442-4
39. Uversky VN, Oldfield CJ, Dunker AK (2008) Intrinsically disordered proteins in human diseases: introducing the D2 concept. Annu Rev Biophys 37:215–46. doi:10.1146/annurev.biophys.37.032807.125924
40. Smith DP, Tew DJ, Hill AF et al (2008) Formation of a high affinity lipid-binding intermediate during the early aggregation phase of alpha-synuclein. Biochemistry 47:1425–34. doi:10.1021/bi701522m
41. Conway KA, Lee S, Rochet J, et al. (2000) Acceleration of oligomerization, not fibrillization, is a shared property of both α-synuclein mutations linked to early-onset Parkinson’s disease: implications for pathogenesis and therapy. 97:571–576.
42. Uversky VN (2002) Natively unfolded proteins: a point where biology waits where biology waits for physics. Protein Sci 11:739–756
43. Lucking CB, Brice A (2000) α-Synuclein and Parkinson’s disease. Cell Mol Life Sci 57:1894–1908
44. Jensen PH, Islam K, Kenney J, Nielsen MS, Power J, Gai WP (2000) Microtubule-associated protein 1B is a component of cortical Lewy bodies and binds alpha-synuclein filaments. J Biol Chem 275:21500–21507
45. Clayton DF, George JM (1998) The synucleins: a family of proteins involved in synaptic functions, plasticity, neurodegeneration and disease. Trends Neurosci 21:249–254
46. Davidson WS, Jonas A, Clayton DF, George JM (1998) Stabilization of alpha-synuclein secondary structure upon binding to synthetic membranes. J Biol Chem 273:9443–9449
47. McLean PJ, Kawamata H, Ribich S, Hyman BT (2000) Membrane association and protein conformation of alpha-synuclein in intact neurons Effect of Parkinson’s disease-linked mutations. J Biol Chem 275:8812–8816
48. George JM, Jin H, Woods WS, Clayton DF (1995) Characterization of a novel protein regulated during the critical period for song learning in the zebra finch. Neuron 15:361–372
49. Kurz A, May C, Schmidt O et al (2012) A53T-alpha-synuclein-overexpression in the mouse nigrostriatal pathway leads to early increase of 14-3-3 epsilon and late increase of GFAP. J Neural Transm 119:297–312. doi:10.1007/s00702-011-0717-3
50. Jensen PH, Hager H, Nielsen S et al (1999) Protein chemistry and structure: α-synuclein binds to tau and stimulates the protein kinase A-catalyzed tau phosphorylation of serine residues 262 and 356. J Biol Chem 274:25481–9
51. Grundke-Iqbal I, Iqbal K, Tung YC, Quinlan M, Wisniewski HM, Binder LI (1986) Abnormal phosphorylation of the microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology. Proc Natl Acad Sci U S A 83(13):4913–7
52. Bayer TA, Jäkälä P, Hartmann T, Egensperger R, Buslei R, Falkai P, Beyreuther K (1999) Neural expression profile of alpha-synuclein in developing human cortex. Neuroreport 10(13):2799–803
53. Stefanis L, Kholodilov N, Rideout HJ, Burke RE, Greene LA (2001) Synuclein-1 is selectively up-regulated in response to nerve growth factor treatment in PC12 cells. J Neurochem 76(4):1165–76
54. Jenco JM, Rawlingson A, Daniels B, Morris AJ (1998) Regulation of phospholipase D2: selective inhibition of mammalian phospholipase D isoenzymes by alpha- and beta-synucleins. Biochemistry 37(14):4901–9
55. Abeliovich A, Schmitz Y, Farinas I, Choi-Lundberg D, Ho WH, Castillo PE, Shinsky N, Verdugo JM, Armanini M, Ryan A, Hynes M, Phillips H, Sulzer D, Rosenthal A (2000) Mice lacking alpha synuclein display functional deficits in the nigrostriatal dopamine system. Neuron 25:239–252
56. Cole NB, Murphy DD, Grider T, Rueter S, Brasaemle D, Nussbaum RL (2002) Lipid droplet binding and oligomerization properties of the Parkinson’s disease protein alpha-synuclein. J Biol Chem 277:6344–6352
57. Yuan J, Zhao Y (2013) Biochemical and biophysical research communications evolutionary aspects of the synuclein super-family and sub-families based on large-scale phylogenetic and group-discrimination analysis. Biochem Biophys Res Commun 441:308–317. doi:10.1016/j.bbrc.2013.09.132
58. 2+ site in the α-synuclein protein of Parkinson’s disease. Biochemistry 50:1771–7. doi:10.1021/bi101912q
59. Levitan K, Chereau D, Cohen SIA, et al. (2012) The aggregation rate of α-synuclein. 411:329–333. doi: 10.1016/j.jmb.2011.05.046
60. Sato H, Kato T, Arawaka S (2013) The role of Ser129 phosphorylation of α-synuclein in neurodegeneration of Parkinson’s disease: a review of in vivo models. Rev Neurosci 24:115–23. doi:10.1515/revneuro-2012-0071
61. Acharya S, Safaie BM, Wongkongkathep P, et al. (2014) Molecular basis for preventing α-synuclein aggregation by a molecular tweezer. J Biol Chem M113.524520–. doi: 10.1074/jbc.M113.524520
62. Gould N, Mor DE, Lightfoot R et al (2014) Evidence of native α-synuclein conformers in the human brain. J Biol Chem 289:7929–34. doi:10.1074/jbc.C113.538249
63. Jakes R, Spillantini MG, Goedert M (1994) Identification of two distinct synucleins from human brain. FEBS Lett 345:27–32
64. Masliah E, Rockenstein E, Veinbergs I et al (2000) Dopaminergic loss and inclusion body formation in alpha-synuclein mice: implications for neurodegenerative disorders. Science 287:1265–9
65. Gadad BS, Britton GB, Rao KS (2011) Targeting oligomers in neurodegenerative disorders: lessons from α-synuclein, tau, and amyloid-β peptide. J Alzheimers Dis 24:223–32
66. Lorenzen N, Nielsen SB, Buell AK et al (2014) The role of stable α-synuclein oligomers in the molecular events underlying amyloid formation. J Am Chem Soc 136:3859–68. doi:10.1021/ja411577t
67. Kayed R, Head E, Thompson JL et al (2003) Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis. Science 300:486–9. doi:10.1126/science.1079469
68. Lindersson E, Beedholm R, Højrup P et al (2004) Proteasomal inhibition by alpha-synuclein filaments and oligomers. J Biol Chem 279:12924–34. doi:10.1074/jbc.M306390200
69. Conway KA, Harper JD, Lansbury PT (2000) Fibrils formed in vitro from r-synuclein and two mutant forms linked to Parkinson’s disease are typical amyloid. Biochemistry 10:2552–63
70. Ding TT, Lee S-J, Rochet J-C, Lansbury PT (2002) Annular alpha-synuclein protofibrils are produced when spherical protofibrils are incubated in solution or bound to brain-derived membranes. Biochemistry 41:10209–17
71. Kahle PJ, Neumann M, Ozmen L et al (2001) Selective insolubility of alpha-synuclein in human Lewy body diseases is recapitulated in a transgenic mouse model. Am J Pathol 159:2215–25
72. Pountney DL, Lowe R, Quilty M et al (2004) Annular alpha-synuclein species from purified multiple system atrophy inclusions. J Neurochem 90:502–12. doi:10.1111/j.1471-4159.2004.02533
73. Wood SJ, Wypych J, Steavenson S et al (1999) Alpha-synuclein fibrillogenesis is nucleation-dependent Implications for the pathogenesis of Parkinson’s disease. J Biol Chem 274:19509–12
74. Arima K, Uéda K, Sunohara N et al (1998) NACP/alpha-synuclein immunoreactivity in fibrillary components of neuronal and oligodendroglial cytoplasmic inclusions in the pontine nuclei in multiple system atrophy. Acta Neuropathol 96:439–44
75. Gai WP, Power JH, Blumbergs PC et al (1999) Alpha-synuclein immunoisolation of glial inclusions from multiple system atrophy brain tissue reveals multiprotein components. J Neurochem 73:2093–100
76. Jensen PH, Islam K, Kenney J et al (2000) Microtubule-associated protein 1B is a component of cortical Lewy bodies and binds alpha-synuclein filaments. J Biol Chem 275:21500–7. doi:10.1074/jbc.M000099200
77. Grazia Spillantini M, Anthony Crowther R, Jakes R et al (1998) Filamentous α-synuclein inclusions link multiple system atrophy with Parkinson’s disease and dementia with Lewy bodies. Neurosci Lett 251:205–208. doi:10.1016/S0304-3940(98)00504-7
78. Bharathi RR, Rao KS (2006) Role of metal in neuronal apoptosis: challenges associated with neurodegeneration. Curr Alz Res 2:311–326
79. Rao KS, Hegde ML, Anitha S, Musicco M, Zucca FA, Turro NJ, Zecca L (2006) Amyloid beta and neuromelanin—toxic or protective molecules? The cellular context makes the difference. Prog Neurobiol 78(6):364–73
80. Hegde ML, Shanmugavelu P, Vengamma B, Sathyanarayana Rao TS, Menon RB, Rao RV, Rao KS (2004) Serum trace elemental levels and the complexity of inter-elemental relationships in patients with Parkinson’s disease. J Trace Elements Med Biol 18:163–171
81. Sanjay Pande MB, Nagabhushan P, Hegde ML, Sathyanarayana Rao TS, Rao KS (2005) An algorithmic approach to understand trace elemental homeostasis in serum samples of Parkinson disease. Comput Biol Med 35:475–493
82. Singh N, Haldar S, Tripathi AK et al (2014) Iron in neurodegenerative disorders of protein misfolding: a case of prion disorders and Parkinson’s disease. Antioxid Redox Signal. doi:10.1089/ars.2014.5874
83. Tamás M, Sharma S, Ibstedt S et al (2014) Heavy metals and metalloids as a cause for protein misfolding and aggregation. Biogeosciences 4:252–267. doi:10.3390/biom4010252
84. Golts N, Snyder H, Frasier M, Theisler C, Choi P, Wolozin B (2002) Magnesium inhibits spontaneous and iron-induced aggregation of alpha-synuclein. J Biol Chem 277:16116–16123
85. Bharathi PN, Rao KS (2008) Mathematical approach to understand the kinetics of alpha-synuclein aggregation: relevance to Parkinson’s disease. Comp Biol Med 38:1084–93
86. Bharathi RKS (2008) Molecular understanding of copper and iron interactions with alpha-synuclein: fluorescence studies. J Mol Neurosci 35:273–281
87. Bharathi ISS, Rao KS (2007) Copper- and iron-induced differential fibril formation in alpha-synuclein: TEM study. Neurosci Lett 424(2):78–82
88. Bharathi RKS (2007) Thermodynamics imprinting reveals differential binding of metals to alpha-synuclein: relevance to Parkinson’s disease. Biochem Biophys Res Commun 59(1):115–20
89. Sung YH, Rospigliosi C, Eliezer D (2006) NMR mapping of copper binding sites in alpha-synuclein. Biochim Biophys Acta 1764:5–12
90. Binolfi A, Rasia RM, Bertoncini CW, Ceolin M, Zweckstetter M, Griesinger C, Jovin TM, Fernández CO (2006) Interaction of alpha-synuclein with divalent metal ions reveals key differences: a link between structure, binding specificity and fibrillation enhancement. J Am Chem Soc 128(30):9893–901
91. Drew SC, Leong SL, Pham CL, Tew DJ, Masters CL, Miles LA, Cappai R, Barnham KJ (2008) Cu2+ binding modes of recombinant alpha-synuclein—insights from EPR spectroscopy. J Am Chem Soc 130(24):7766–73
92. Lee JC, Gray HB, Winkler JR (2008) Copper(II) binding to alpha-synuclein, the Parkinson’s protein. J Am Chem Soc 130(22):6898–9
93. Kostka M, Högen T, Danzer KM, Levin J, Habeck M, Wirth A, Wagner R, Glabe CG, Finger S, Heinzelmann U, Garidel P, Duan W, Ross CA, Kretzschmar H, Giese A (2008) Single particle characterization of iron-induced pore-forming alpha-synuclein oligomers. J Biol Chem 283(16):10992–1003
94. Liu LL, Franz KJ (2007) Phosphorylation-dependent metal binding by alpha-synuclein peptide fragments. J Biol Inorg Chem 12:232–237