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Role of α-synuclein penetration into the membrane in the mechanisms of oligomer pore formation

Igor F. Tsigelny^1,2,3,
Yuriy Sharikov^1,3,
Wolfgang Wrasidlo²,
Tania Gonzalez³,
Paula A. Desplats³,
Leslie Crews³,
Brian Spencer³,
Eliezer Masliah^3,4

Article first published online: 27 FEB 2012

DOI: 10.1111/j.1742-4658.2012.08489.x

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FEBS Journal

Volume 279, Issue 6, pages 1000–1013, March 2012

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How to Cite

Tsigelny, I. F., Sharikov, Y., Wrasidlo, W., Gonzalez, T., Desplats, P. A., Crews, L., Spencer, B. and Masliah, E. (2012), Role of α-synuclein penetration into the membrane in the mechanisms of oligomer pore formation. FEBS Journal, 279: 1000–1013. doi: 10.1111/j.1742-4658.2012.08489.x

Author Information

¹
San Diego Supercomputer Center, University of California, San Diego, La Jolla, CA, USA
²
Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA
³
Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA
⁴
Department of Pathology, University of California, San Diego, La Jolla, CA, USA

^*Dr Eliezer Masliah, Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093-0624, USA Fax: +858 534 6232 Tel: +858 534 8992 E-mail: emasliah@ucsd.edu

Publication History

Issue published online: 12 MAR 2012
Article first published online: 27 FEB 2012
Accepted manuscript online: 17 JAN 2012 05:41PM EST
(Received 28 October 2011, revised 24 December 2011, accepted 5 January 2012)

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References

1
Wright PE & Dyson HJ (1999) Intrinsically unstructured proteins: re-assessing the protein structure-function paradigm. J Mol Biol 293, 321–331.
2
Lansbury PT Jr (1999) Evolution of amyloid: what normal protein folding may tell us about fibrillogenesis and disease. Proc Natl Acad Sci USA 96, 3342–3344.
3
Chandra S, Gallardo G, Fernandez-Chacon R, Schluter OM & Sudhof TC (2005) Alpha-synuclein cooperates with CSPalpha in preventing neurodegeneration. Cell 123, 383–396.
4
Burre J, Sharma M, Tsetsenis T, Buchman V, Etherton MR & Sudhof TC (2010) Alpha-synuclein promotes SNARE-complex assembly in vivo and in vitro. Science 329, 1663–1667.
5
Lashuel HA, Petre BM, Wall J, Simon M, Nowak RJ, Walz T & Lansbury PT Jr (2002) Alpha-synuclein, especially the Parkinson’s disease-associated mutants, forms pore-like annular and tubular protofibrils. J Mol Biol 322, 1089–1102.
6
Trojanowski JQ, Goedert M, Iwatsubo T & Lee VM (1998) Fatal attractions: abnormal protein aggregation and neuron death in Parkinson’s disease and Lewy body dementia. Cell Death Differ 5, 832–837.
7
Wakabayashi K, Hayashi S, Kakita A, Yamada M, Toyoshima Y, Yoshimoto M & Takahashi H (1998) Accumulation of alpha-synuclein/NACP is a cytopathological feature common to Lewy body disease and multiple system atrophy. Acta Neuropathol 96, 445–452.
8
Uversky VN (2010) Mysterious oligomerization of the amyloidogenic proteins. FEBS J 277, 2940–2953.
Direct Link:
9
Hong DP, Han S, Fink AL & Uversky VN (2011) Characterization of the non-fibrillar α-synuclein oligomers. Protein Pept Lett 18, 230–240.
10
Uversky VN & Eliezer D (2009) Biophysics of Parkinson’s disease: structure and aggregation of alpha-synuclein. Curr Protein Pept Sci 10, 483–499.
11
Snyder H & Wolozin B (2004) Pathological proteins in Parkinson’s disease: focus on the proteasome. J Mol Neurosci 24, 425–442.
12
Spillantini M, Schmidt M, Lee V-Y, Trojanowski J, Jakes R & Goedert M (1997) a-Synuclein in Lewy bodies. Nature 388, 839–840.
13
Takeda A, Mallory M, Sundsmo M, Honer W, Hansen L & Masliah E (1998) Abnormal accumulation of NACP/a-synuclein in neurodegenerative disorders. Am J Pathol 152, 367–372.
14
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.
15
Lippa CF, Duda JE, Grossman M, Hurtig HI, Aarsland D, Boeve BF, Brooks DJ, Dickson DW, Dubois B, Ernre M et al. (2007) DLB and PDD boundary issues: diagnosis, treatment, molecular pathology, and biomarkers. Neurology 68, 812–819.
16
Bennett MC (2005) The role of alpha-synuclein in neurodegenerative diseases. Pharmacol Ther 105, 311–331.
17
Uchikado H, Lin WL, DeLucia MW & Dickson DW (2006) Alzheimer disease with amygdala Lewy bodies: a distinct form of alpha-synucleinopathy. J Neuropathol Exp Neurol 65, 685–697.
18
Tan EK & Skipper LM (2007) Pathogenic mutations in Parkinson disease. Hum Mutat 28, 641–653.
Direct Link:
19
Kruger R, Kuhn W, Muller T, Woitalla D, Graeber M, Kosel S, Przuntek H, Epplen J, Schols L & Reiss O (1998) Ala30Pro mutation in the gene encoding a-synuclein in Parkinsons’s disease. Nat Genet 18, 106–108.
20
Polymeropoulos M, Lavedan C, Leroy E, Ide S, Dehejia A, Dutra A, Pike B, Root H, Rubenstein J, Boyer R et al. (1997) Mutation in the a-synuclein gene identified in families with Parkinson’s disease. Science 276, 2045–2047.
21
Singleton AB, Farrer M, Johnson J, Singleton A, Hague S, Kachergus J, Hulihan M, Peuralinna T, Dutra A, Nussbaum R et al. (2003) alpha-Synuclein locus triplication causes Parkinson’s disease. Science 302, 841.
22
Conway KA, Lee SJ, Rochet JC, Ding TT, Williamson RE & Lansbury PT Jr (2000) Acceleration of oligomerization, not fibrillization, is a shared property of both alpha-synuclein mutations linked to early-onset Parkinson’s disease: implications for pathogenesis and therapy. Proc Natl Acad Sci USA 97, 571–576.
23
Winner B, Jappelli R, Maji SK, Desplats PA et al. (2011) In vivo demonstration that alpha-synuclein oligomers are toxic. Proc Natl Acad Sci USA 108, 4194–4195.
24
Giehm L, Svergun DI, Otzen DE & Vestergaard B (2011) Low-resolution structure of a vesicle disrupting α-synuclein oligomer that accumulates during fibrillation. Proc Natl Acad Sci USA 108, 3246–32451.
25
Tsigelny IF, Bar-On P, Sharikov Y, Crews L, Hashimoto M, Miller MA, Keller SH, Platoshyn O, Yuan JX & Masliah E (2007) Dynamics of alpha-synuclein aggregation and inhibition of pore-like oligomer development by beta-synuclein. Febs J 274, 1862–1877.
Direct Link:
26
Bortolus M, Tombolato F, Tessari I et al. (2008) Broken helix in vesicle and micelle-bound alpha-synuclein: insights from site-directed spin labeling-EPR experiments and MD simulations. J Am Chem Soc 130, 6690–6691.
27
Perlmutter JD, Braun AR & Sachs JN (2009) Experimental verification of lipid bilayer structure through multi-scale modeling. Biochim Biophys Acta 88, 2284–22890.
28
van Rooijen BD, Claessens MM & Subramaniam V (2010) Membrane permeabilization by oligomeric α-synuclein: in search of the mechanism. PLoS One 5, e14292.
29
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, 350–357.
30
Walsh DM, Klyubin I, Fadeeva JV, Rowan MJ & Selkoe DJ (2002) Amyloid-beta oligomers: their production, toxicity and therapeutic inhibition. Biochem Soc Trans 30, 552–557.
31
Haass C & Selkoe DJ (2007) Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer’s amyloid beta-peptide. Nat Rev Mol Cell Biol 8, 101–112.
32
Norris EH, Giasson BI, Ischiropoulos H & Lee VM (2003) Effects of oxidative and nitrative challenges on alpha-synuclein fibrillogenesis involve distinct mechanisms of protein modifications. J Biol Chem 278, 27230–27240.
33
Beyer K (2006) Alpha-synuclein structure, posttranslational modification and alternative splicing as aggregation enhancers. Acta Neuropathol (Berl) 112, 237–251.
34
Perrin RJ, Woods WS, Clayton DF & George JM (2001) Exposure to long chain polyunsaturated fatty acids triggers rapid multimerization of synucleins. J Biol Chem 276, 41958–41962.
35
Assayag K, Yakunin E, Loeb V, Selkoe DJ & Sharon R (2007) Polyunsaturated fatty acids induce alpha-synuclein-related pathogenic changes in neuronal cells. Am J Pathol 171, 2000–2011.
36
Beyer K (2007) Mechanistic aspects of Parkinson’s disease: alpha-synuclein and the biomembrane. Cell Biochem Biophys 47, 285–299.
37
Butterfield SM & Lashuel HA (2010) Amyloidogenic protein-membrane interactions: mechanistic insight from model systems. Angew Chem Int Ed Engl 49, 5628–5654.
Direct Link:
38
Furukawa K, Matsuzaki-Kobayashi M, Hasegawa T, Kikuchi A, Sugeno N, Itoyama Y, Wang Y, Yao PJ, Bushlin I & Takeda A (2006) Plasma membrane ion permeability induced by mutant alpha-synuclein contributes to the degeneration of neural cells. J Neurochem 97, 1071–1077.
Direct Link:
39
Quist A, Doudevski I, Lin H, Azimova R, Ng D, Frangione B, Kagan B, Ghiso J & Lal R (2005) Amyloid ion channels: a common structural link for protein-misfolding disease. Proc Natl Acad Sci USA 102, 10427–10432.
40
Danzer KM, Haasen D, Karow AR, Moussaud S, Habeck M, Giese A, Kretzschmar H, Hengerer B & Kostka M (2007) Different species of alpha-synuclein oligomers induce calcium influx and seeding. J Neurosci 27, 9220–9232.
41
Kim HY, Cho MK & Kumar A (2009) Structural properties of pore-forming oligomers of alpha-synuclein. J Am Chem Soc 131, 17482–17489.
42
Ulmer TS, Bax A, Cole NB & Nussbaum RL (2005) Structure and dynamics of micelle-bound human alpha-synuclein. J Biol Chem 280, 9595–9603.
43
Sharikov Y, Walker RC, Greenberg J, Kouznetsova V, Nigam SK, Miller MA, Masliah E & Tsigelny IF (2008) MAPAS: a tool for predicting membrane-contacting protein surfaces. Nat Methods 5, 119.
44
Cserzo M, Wallin E, Simon I, von Heijne G & Elofsson A (1997) Prediction of transmembrane alpha-helices in prokaryotic membrane proteins: the dense alignment surface method. Protein Eng 10, 673–676.
45
Cserzo M, Bernassau JM, Simon I & Maigret B (1994) New alignment strategy for transmembrane proteins. J Mol Biol 243, 388–396.
46
Anderson VL, Ramlall TF, Rospigliosi CC, Webb WW & Eliezer D (2010) Identification of a helical intermediate in trifluoroethanol-induced alpha-synuclein aggregation. Proc Natl Acad Sci USA 107, 18850–18855.
47
Hashimoto M, Rockenstein E, Mante M, Mallory M & Masliah E (2001) beta-Synuclein inhibits alpha-synuclein aggregation: a possible role as an anti-parkinsonian factor. Neuron 32, 213–223.
48
van Rooijen BD, Claessens MM & Subramaniam V (2009) Lipid bilayer disruption by oligomeric alpha-synuclein depends on bilayer charge and accessibility of the hydrophobic core. Biochim Biophys Acta 1788, 1271–1278.
49
Shvadchak VV, Falomir-Lockhart LJ, Yushchenko DA & Jovin TM (2011) Specificity and kinetics of α-synuclein binding to model membranes determined with fluorescent esipt probe. J Biol Chem 286, 13023–13032.
50
Lashuel HA, Hartley D, Petre BM et al. (2002) Neurodegenerative disease: amyloid pores from pathogenic mutations. Nature 418, 291.
51
Yoon J, Jang S, Lee K & Shin S (2009) Simulation studies on the stabilities of aggregates formed by fibril-forming segments of alpha-Synuclein. J Biomol Struct Dyn 27, 259–270.
52
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, 30649–30652.
53
Reynolds NP, Soragni A, Rabe M & Verdes D (2011) The mechanism of membrane interaction and disruption by alpha-Synuclein. J Am Chem Soc 133, 19366–19375.
54
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, 444–450.
55
Tsigelny IF, Crews L, Desplats P, Shaked GM, Sharikov Y, Mizuno H, Spencer B, Rockenstein E, Trejo M, Platoshyn O et al. (2008) Mechanisms of hybrid oligomer formation in the pathogenesis of combined Alzheimer’s and Parkinson’s diseases. PLoS One 3, e3135.
56
Kalé L, Skeel R, Bhandarkar M, Brunner R, Gursoy A, Krawetz N, Phillips J, Shinozaki A, Varadarajan K & Schulten K (1999) NAMD2: greater scalability for parallel molecular dynamics. J Comp Physics 151, 282–312.
57
Feller S & MacKerell A (2000) An improved empirical potential energy function for molecular simulations of phospholipids. J Phys Chem B 104, 7510–7515.
58
Tu K, Tobias DJ & Klein ML (1995) Constant pressure and temperature molecular dynamics simulation of a fully hydrated liquid crystal phase dipalmitoylphosphatidylcholine bilayer. Biophys J 69, 2558–2562.
59
Feller S, Zhang Y, Pastor RW & Brooks BR (1995) Constant pressure molecular dynamics simulation: the Langevin piston method. J Chem Phys 103, 4613–4621.
60
Essmann U, Perera L & Berkowitz ML (1995) A smooth particle mesh Ewald method. J Chem Phys 103, 8577–8593.
61
Tuckerman M, Berne BJ & Martyna GJ (1992) Reversible multiple time scale molecular dynamics. J Chem Phys 97, 1990–2001.
62
Grubmüller H, Heller H, Windemuth A & Schulten K (1991) Generalized Verlet algorithm for efficient molecular dynamics simulations with long-range interactions. Mol Simul 6, 121–142.
- CrossRef
63
Naldini L, Blomer U, Gage FH, Trono D & Verma IM (1996) Efficient transfer, integration, and sustained long-term expression of the transgene in adult rat brains injected with a lentiviral vector. Proc Natl Acad Sci USA 93, 11382–11388.
64
Tiscornia G, Singer O, Ikawa M & Verma IM (2003) A general method for gene knockdown in mice by using lentiviral vectors expressing small interfering RNA. Proc Natl Acad Sci USA 100, 1844–1848.
65
Hashimoto M, Rockenstein E, Mante M, Crews L, Bar-On P, Gage FH, Marr R & Masliah E (2004) An antiaggregation gene therapy strategy for Lewy body disease utilizing beta-synuclein lentivirus in a transgenic model. Gene Ther 11, 1713–1723.
66
Masliah E, Rockenstein E, Veinbergs I, Mallory M, Hashimoto M, Takeda A, Sagara Y, Sisk A & Mucke L (2000) Dopaminergic loss and inclusion body formation in alpha-synuclein mice: implications for neurodegenerative disorders. Science 287, 1265–1269.
67
Ford MG, Pearse BM, Higgins MK, Vallis Y, Owen DJ, Gibson A, Hopkins CR, Evans PR, McMahon HT (2001) Simultaneous binding of PtdIns(4,5)P2 and clathrin by AP180 in the nucleation of clathrin lattices on membranes. Science 291, 1051–1055.

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Role of α-synuclein penetration into the membrane in the mechanisms of oligomer pore formation

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