Hostname: page-component-7f64f4797f-kjzhn Total loading time: 0 Render date: 2025-11-04T14:12:21.180Z Has data issue: false hasContentIssue false
  • English
  • Français

Biophysical groundwork as a hinge to unravel the biology of α-synuclein aggregation and toxicity

Published online by Cambridge University Press:  21 January 2014

Nicoletta Plotegher ,
Elisa Greggio ,
Marco Bisaglia  and
Luigi Bubacco
Nicoletta Plotegher
Affiliation:
Molecular Physiology and Biophysics Unit, Department of Biology, University of Padova, Padova, Italy
Elisa Greggio
Affiliation:
Molecular Physiology and Biophysics Unit, Department of Biology, University of Padova, Padova, Italy
Marco Bisaglia
Affiliation:
Molecular Physiology and Biophysics Unit, Department of Biology, University of Padova, Padova, Italy
Luigi Bubacco*
Affiliation:
Molecular Physiology and Biophysics Unit, Department of Biology, University of Padova, Padova, Italy
*
* Author for Correspondence: Luigi Bubacco, Molecular Physiology and Biophysics Unit, Department of Biology, University of Padova, Via U. Bassi 58B, 35121 Padova, Italy. Fax: +390498276300; Email: luigi.bubacco@unipd.it
Get access Rights & Permissions [Opens in a new window]

Abstract

Alpha-synuclein (aS) and its aggregation properties are central in the development and spread of Parkinson's disease. Point mutations and multiplications of the SNCA gene encoding aS cause autosomal dominant forms of the disorder. Moreover, protein inclusions found in the surviving neurons of parkinsonian brains consist mainly of a fibrillar form of aS. Aggregates of aS, which form a transient, complex and heterogeneous ensemble, participate in a wide variety of toxic mechanisms that may be amplified by aS spreading among neighbouring neurons. Recently, significant effort has been directed into the study of the aS aggregation process and the impact of aS aggregates on neuron survival. In this review, we present state-of-the-art biophysical studies on the aS aggregation process in vitro and in cellular models. We comprehensively review the new insights generated by the recent biophysical investigations, which could provide a solid basis from which to design future biomedical studies. The diverse cellular models of aS toxicity and their potential use in the biophysical investigation are also discussed.

Information

Type
Review Article
Information
Quarterly Reviews of Biophysics , Volume 47 , Issue 1 , February 2014 , pp. 1 - 48
Copyright
Copyright © Cambridge University Press 2014 

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

Article purchase

Temporarily unavailable

References

9. References

Abeliovich, A., Schmitz, Y., Farinas, 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. & Rosenthal, A. (2000). Mice lacking alpha-synuclein display functional deficits in the nigrostriatal dopamine system. Neuron 25(1), 239–252.Google Scholar
Alim, M. A., Ma, Q. L., Takeda, K., Aizawa, T., Matsubara, M., Nakamura, M., Asada, A., Saito, T., Kaji, H., Yoshii, M., Hisanaga, S. & Ueda, K. (2004). Demonstration of a role for alpha-synuclein as a functional microtubule-associated protein. Journal of Alzheimer's Disease 6(4), 435–442; discussion 443–439.Google Scholar
Allison, J. R., Varnai, P., Dobson, C. M. & Vendruscolo, M. (2009). Determination of the free energy landscape of alpha-synuclein using spin label nuclear magnetic resonance measurements. Journal of American Chemical Socirty 131(51), 18314–18326.Google Scholar
Alvarez-Erviti, L., Couch, Y., Richardson, J., Cooper, J. M. & Wood, M. J. (2011a). Alpha-synuclein release by neurons activates the inflammatory response in a microglial cell line. Neuroscience Research 69(4), 337–342.CrossRefGoogle Scholar
Alvarez-Erviti, L., Seow, Y., Schapira, A. H., Gardiner, C., Sargent, I. L., Wood, M. J. & Cooper, J. M. (2011b). Lysosomal dysfunction increases exosome-mediated alpha-synuclein release and transmission. Neurobiology of Disease 42(3), 360–367.Google Scholar
Anderson, J. P., Walker, D. E., Goldstein, J. M., De Laat, R., Banducci, K., Caccavello, R. J., Barbour, R., Huang, J., Kling, K., Lee, M., Diep, L., Keim, P. S., Shen, X., Chataway, T., Schlossmacher, M. G., Seubert, P., Schenk, D., Sinha, S., Gai, W. P. & Chilcote, T. J. (2006). Phosphorylation of Ser-129 is the dominant pathological modification of alpha-synuclein in familial and sporadic Lewy body disease. Journal of Biological Chemistry 281(40), 29739–29752.Google Scholar
Apetri, M. M., Maiti, N. C., Zagorski, M. G., Carey, P. R. & Anderson, V. E. (2006). Secondary structure of alpha-synuclein oligomers: characterization by Raman and atomic force microscopy. Journal of Molecular Biology 355(1), 63–71.Google Scholar
Auluck, P. K., Caraveo, G. & Lindquist, S. (2010). alpha-Synuclein: membrane interactions and toxicity in Parkinson's disease. Annual Review of Cell and Developmental Biology 26, 211–233.CrossRefGoogle ScholarPubMed
Auluck, P. K., Chan, H. Y., Trojanowski, J. Q., Lee, V. M. & Bonini, N. M. (2002). Chaperone suppression of alpha-synuclein toxicity in a Drosophila model for Parkinson's disease. Science 295(5556), 865–868.CrossRefGoogle Scholar
Bartels, T., Ahlstrom, L. S., Leftin, A., Kamp, F., Haass, C., Brown, M. F. & Beyer, K. (2010). The N-terminus of the intrinsically disordered protein alpha-synuclein triggers membrane binding and helix folding. Biophysics Journal 99(7), 2116–2124.Google Scholar
Bartels, T., Choi, J. G. & Selkoe, D. J. (2011). alpha-Synuclein occurs physiologically as a helically folded tetramer that resists aggregation. Nature 477(7362), 107–110.CrossRefGoogle ScholarPubMed
Berman, S. B. & Hastings, T. G. (1999). Dopamine oxidation alters mitochondrial respiration and induces permeability transition in brain mitochondria: implications for Parkinson's disease. Journal of Neurochemistry 73(3), 1127–1137.Google Scholar
Bertoncini, C. W., Jung, Y. S., Fernandez, C. O., Hoyer, W., Griesinger, C., Jovin, T. M. & Zweckstetter, M. (2005). Release of long-range tertiary interactions potentiates aggregation of natively unstructured alpha-synuclein. Proceedings of the National Academy of Sciences United States of America 102(5), 1430–1435.CrossRefGoogle ScholarPubMed
Bhak, G., Lee, J. H., Hahn, J. S. & Paik, S. R. (2009). Granular assembly of alpha-synuclein leading to the accelerated amyloid fibril formation with shear stress. PLoS ONE 4(1), e4177.Google Scholar
Bieschke, J., Russ, J., Friedrich, R. P., Ehrnhoefer, D. E., Wobst, H., Neugebauer, K. & Wanker, E. E. (2010). EGCG remodels mature alpha-synuclein and amyloid-beta fibrils and reduces cellular toxicity. Proceedings of the National Academy of Sciences United States of America 107(17), 7710–7715.CrossRefGoogle ScholarPubMed
Binolfi, A., Theillet, F. X. & Selenko, P. (2012). Bacterial in-cell NMR of human alpha-synuclein: a disordered monomer by nature? Biochemical Society Transaction, 40(5), 950–954.Google Scholar
Bisaglia, M., Mammi, S. & Bubacco, L. (2007). Kinetic and structural analysis of the early oxidation products of dopamine: analysis of the interactions with alpha-synuclein. Journal of Biological Chemistry 282(21), 15597–15605.Google Scholar
Bisaglia, M., Tessari, I., Mammi, S. & Bubacco, L. (2009). Interaction between alpha-synuclein and metal ions, still looking for a role in the pathogenesis of Parkinson's disease. Neuromolecular Medicine 11(4), 239–251.Google Scholar
Borbat, P., Ramlall, T. F., Freed, J. H. & Eliezer, D. (2006). Inter-helix distances in lysophospholipid micelle-bound alpha-synuclein from pulsed ESR measurements. Journal of the American Chemical Society 128(31), 10004–10005.Google Scholar
Braak, H., Del Tredici, K., Rub, U., De Vos, R. A., Jansen Steur, E. N. & Braak, E. (2003). Staging of brain pathology related to sporadic Parkinson's disease. Neurobiology of Aging 24(2), 197–211.CrossRefGoogle ScholarPubMed
Brooks, D. J. (1998). The early diagnosis of Parkinson's disease. Annals of Neurology 44(3 Suppl 1), S10–S18.Google Scholar
Brucale, M., Sandal, M., Di Maio, S., Rampioni, A., Tessari, I., Tosatto, L., Bisaglia, M., Bubacco, L. & Samori, B. (2009). Pathogenic mutations shift the equilibria of alpha-synuclein single molecules towards structured conformers. ChemBioChem 10(1), 176–183.CrossRefGoogle ScholarPubMed
Burke, W. J., Kumar, V. B., Pandey, N., Panneton, W. M., Gan, Q., Franko, M. W., O'Dell, M., Li, S. W., Pan, Y., Chung, H. D. & Galvin, J. E. (2008). Aggregation of alpha-synuclein by DOPAL, the monoamine oxidase metabolite of dopamine. Acta Neuropathology 115(2), 193–203.Google Scholar
Burre, J., Sharma, M., Tsetsenis, T., Buchman, V., Etherton, M. R. & Sudhof, T. C. (2010). Alpha-synuclein promotes SNARE-complex assembly in vivo and in vitro . Science 329(5999), 1663–1667.Google Scholar
Bussell, R. Jr., Ramlall, T. F. & Eliezer, D. (2005). Helix periodicity, topology, and dynamics of membrane-associated alpha-synuclein. Protein Science 14(4), 862–872.Google Scholar
Butterfield, S. M. & Lashuel, H. A. (2010). Amyloidogenic protein–membrane interactions: mechanistic insight from model systems. Angewandte Chemie International Edition English 49(33), 5628–5654.Google Scholar
Buttner, S., Delay, C., Franssens, V., Bammens, T., Ruli, D., Zaunschirm, S., De Oliveira, R. M., Outeiro, T. F., Madeo, F., Buee, L., Galas, M. C. & Winderickx, J. (2010). Synphilin-1 enhances alpha-synuclein aggregation in yeast and contributes to cellular stress and cell death in a Sir2-dependent manner. PLoS ONE 5(10), e13700.Google Scholar
Cappai, R., Leck, S. L., Tew, D. J., Williamson, N. A., Smith, D. P., Galatis, D., Sharples, R. A., Curtain, C. C., Ali, F. E., Cherny, R. A., Culvenor, J. G., Bottomley, S. P., Masters, C. L., Barnham, K. J. & Hill, A. F. (2005). Dopamine promotes alpha-synuclein aggregation into SDS-resistant soluble oligomers via a distinct folding pathway. FASEB Journal 19(10), 1377–1379.Google Scholar
Casuso, I., Rico, F. & Scheuring, S. (2011). Biological AFM: where we come from – where we are – where we may go. Journal of Molecular Recognition 24(3), 406–413.Google Scholar
Chartier-Harlin, M. C., Kachergus, J., Roumier, C., Mouroux, V., Douay, X., Lincoln, S., Levecque, C., Larvor, L., Andrieux, J., Hulihan, M., Waucquier, N., Defebvre, L., Amouyel, P., Farrer, M. & Destee, A. (2004). Alpha-synuclein locus duplication as a cause of familial Parkinson's disease. Lancet 364(9440), 1167–1169.Google Scholar
Chen, M., Margittai, M., Chen, J. & Langen, R. (2007). Investigation of alpha-synuclein fibril structure by site-directed spin labeling. Journal of Biological Chemistry 282(34), 24970–24979.Google Scholar
Cho, M. K., Nodet, G., Kim, H. Y., Jensen, M. R., Bernado, P., Fernandez, C. O., Becker, S., Blackledge, M. & Zweckstetter, M. (2009). Structural characterization of alpha-synuclein in an aggregation prone state. Protein Science 18(9), 1840–1846.Google Scholar
Choi, B. K., Choi, M. G., Kim, J. Y., Yang, Y., Lai, Y., Kweon, D. H., Lee, N. K. & Shin, Y. K. (2013). Large alpha-synuclein oligomers inhibit neuronal SNARE-mediated vesicle docking. Proceedings of the National Academy of Sciences United States of America 110(10), 4087–4092.CrossRefGoogle ScholarPubMed
Clayton, D. F. & George, J. M. (1998). The synucleins: a family of proteins involved in synaptic function, plasticity, neurodegeneration and disease. Trends in Neuroscience 21(6), 249–254.Google Scholar
Clayton, D. F. & George, J. M. (1999). Synucleins in synaptic plasticity and neurodegenerative disorders. Journal of Neuroscience Research 58(1), 120–129.3.0.CO;2-E>CrossRefGoogle ScholarPubMed
Codolo, G., Plotegher, N., Pozzobon, T., Brucale, M., Tessari, I., Bubacco, L. & De Bernard, M. (2013). Triggering of inflammasome by aggregated alpha-synuclein, an inflammatory response in synucleinopathies. PLoS ONE 8(1), e55375.Google Scholar
Cohlberg, J. A., Li, J., Uversky, V. N. & Fink, A. L. (2002). Heparin and other glycosaminoglycans stimulate the formation of amyloid fibrils from alpha-synuclein in vitro . Biochemistry 41(5), 1502–1511.CrossRefGoogle ScholarPubMed
Colla, E., Jensen, P. H., Pletnikova, O., Troncoso, J. C., Glabe, C. & Lee, M. K. (2012). Accumulation of toxic alpha-synuclein oligomer within endoplasmic reticulum occurs in alpha-synucleinopathy in vivo . Journal of Neuroscience 32(10), 3301–3305.Google Scholar
Comellas, G., Lemkau, L. R., Nieuwkoop, A. J., Kloepper, K. D., Ladror, D. T., Ebisu, R., Woods, W. S., Lipton, A. S., George, J. M. & Rienstra, C. M. (2011). Structured regions of alpha-synuclein fibrils include the early-onset Parkinson's disease mutation sites. Journal of Molecular Biology 411(4), 881–895.Google Scholar
Comellas, G., Lemkau, L. R., Zhou, D. H., George, J. M. & Rienstra, C. M. (2012). Structural intermediates during alpha-synuclein fibrillogenesis on phospholipid vesicles. Journal of the American Chemical Society 134(11), 5090–5099.Google Scholar
Conway, K. A., Harper, J. D. & Lansbury, P. T. Jr. (2000). Fibrils formed in vitro from alpha-synuclein and two mutant forms linked to Parkinson's disease are typical amyloid. Biochemistry 39(10), 2552–2563.Google Scholar
Cremades, N., Cohen, S. I., Deas, E., Abramov, A. Y., Chen, A. Y., Orte, A., Sandal, M., Clarke, R. W., Dunne, P., Aprile, F. A., Bertoncini, C. W., Wood, N. W., Knowles, T. P., Dobson, C. M. & Klenerman, D. (2012). Direct observation of the interconversion of normal and toxic forms of alpha-synuclein. Cell 149(5), 1048–1059.Google Scholar
Cuervo, A. M., Stefanis, L., Fredenburg, R., Lansbury, P. T. & Sulzer, D. (2004). Impaired degradation of mutant alpha-synuclein by chaperone-mediated autophagy. Science 305(5688), 1292–1295.Google Scholar
Danzer, K. M., Kranich, L. R., Ruf, W. P., Cagsal-Getkin, O., Winslow, A. R., Zhu, L., Vanderburg, C. R. & Mclean, P. J. (2012). Exosomal cell-to-cell transmission of alpha synuclein oligomers. Molecular Neurodegeneration 7, 42.Google Scholar
Danzer, K. M., Krebs, S. K., Wolff, M., Birk, G. & Hengerer, B. (2009). Seeding induced by alpha-synuclein oligomers provides evidence for spreading of alpha-synuclein pathology. Journal of Neurochemistry 111(1), 192–203.CrossRefGoogle ScholarPubMed
Davidson, W. S., Jonas, A., Clayton, D. F. & George, J. M. (1998). Stabilization of alpha-synuclein secondary structure upon binding to synthetic membranes. Journal of Biological Chemistry 273(16), 9443–9449.Google Scholar
De Franceschi, G., Frare, E., Pivato, M., Relini, A., Penco, A., Greggio, E., Bubacco, L., Fontana, A. & De Laureto, P. P. (2011). Structural and morphological characterization of aggregated species of alpha-synuclein induced by docosahexaenoic acid. Journal of Biological Chemistry 286(25), 22262–22274.Google Scholar
Dedmon, M. M., Christodoulou, J., Wilson, M. R. & Dobson, C. M. (2005a). Heat shock protein 70 inhibits alpha-synuclein fibril formation via preferential binding to prefibrillar species. Journal of Biological Chemistry 280(15), 14733–14740.Google Scholar
Dedmon, M. M., Lindorff-Larsen, K., Christodoulou, J., Vendruscolo, M. & Dobson, C. M. (2005b). Mapping long-range interactions in alpha-synuclein using spin-label NMR and ensemble molecular dynamics simulations. Journal of the American Chemical Society 127(2), 476–477.Google Scholar
Der-Sarkissian, A., Jao, C. C., Chen, J. & Langen, R. (2003). Structural organization of alpha-synuclein fibrils studied by site-directed spin labeling. Journal of Biological Chemistry 278(39), 37530–37535.Google Scholar
Desplats, P., Lee, H. J., Bae, E. J., Patrick, C., Rockenstein, E., Crews, L., Spencer, B., Masliah, E. & Lee, S. J. (2009). Inclusion formation and neuronal cell death through neuron-to-neuron transmission of alpha-synuclein. Proceedings of the National Academy of Sciences United States of America 106(31), 13010–13015.Google Scholar
Devi, L., Raghavendran, V., Prabhu, B. M., Avadhani, N. G. & Anandatheerthavarada, H. K. (2008). Mitochondrial import and accumulation of alpha-synuclein impair complex I in human dopaminergic neuronal cultures and Parkinson disease brain. Journal of Biological Chemistry 283(14), 9089–9100.Google Scholar
Dickson, D. W. (2007). Linking selective vulnerability to cell death mechanisms in Parkinson's disease. American Journal of Pathology 170(1), 16–19.CrossRefGoogle ScholarPubMed
Dobson, C. M. (1999). Protein misfolding, evolution and disease. Trends in Biochemical Science 24(9), 329–332.Google Scholar
Duda, J. E., Giasson, B. I., Chen, Q., Gur, T. L., Hurtig, H. I., Stern, M. B., Gollomp, S. M., Ischiropoulos, H., Lee, V. M. & Trojanowski, J. Q. (2000). Widespread nitration of pathological inclusions in neurodegenerative synucleinopathies. American Journal of Pathology 157(5), 1439–1445.CrossRefGoogle ScholarPubMed
Dusa, A., Kaylor, J., Edridge, S., Bodner, N., Hong, D. P. & Fink, A. L. (2006). Characterization of oligomers during alpha-synuclein aggregation using intrinsic tryptophan fluorescence. Biochemistry 45(8), 2752–2760.Google Scholar
Ebrahimi-Fakhari, D., Wahlster, L. & Mclean, P. J. (2012). Protein degradation pathways in Parkinson's disease: curse or blessing. Acta Neuropathology 124(2), 153–172.Google Scholar
El-Agnaf, O. M., Paleologou, K. E., Greer, B., Abogrein, A. M., King, J. E., Salem, S. A., Fullwood, N. J., Benson, F. E., Hewitt, R., Ford, K. J., Martin, F. L., Harriott, P., Cookson, M. R. & Allsop, D. (2004). A strategy for designing inhibitors of alpha-synuclein aggregation and toxicity as a novel treatment for Parkinson's disease and related disorders. FASEB Journal 18(11), 1315–1317.CrossRefGoogle ScholarPubMed
Engelender, S., Kaminsky, Z., Guo, X., Sharp, A. H., Amaravi, R. K., Kleiderlein, J. J., Margolis, R. L., Troncoso, J. C., Lanahan, A. A., Worley, P. F., Dawson, V. L., Dawson, T. M. & Ross, C. A. (1999). Synphilin-1 associates with alpha-synuclein and promotes the formation of cytosolic inclusions. Nature Genetics 22(1), 110–114.Google Scholar
Esposito, A., Dohm, C. P., Kermer, P., Bahr, M. & Wouters, F. S. (2007). alpha-Synuclein and its disease-related mutants interact differentially with the microtubule protein tau and associate with the actin cytoskeleton. Neurobiology of Disease 26(3), 521–531.CrossRefGoogle ScholarPubMed
Fauvet, B., Fares, M. B., Samuel, F., Dikiy, I., Tandon, A., Eliezer, D. & Lashuel, H. A. (2012a). Characterization of semisynthetic and naturally Nalpha-acetylated alpha-synuclein in vitro and in intact cells: implications for aggregation and cellular properties of alpha-synuclein. Journal of Biological Chemistry 287(34), 28243–28262.Google Scholar
Fauvet, B., Mbefo, M. K., Fares, M. B., Desobry, C., Michael, S., Ardah, M. T., Tsika, E., Coune, P., Prudent, M., Lion, N., Eliezer, D., Moore, D. J., Schneider, B., Aebischer, P., El-Agnaf, O. M., Masliah, E. & Lashuel, H. A. (2012b). alpha-Synuclein in central nervous system and from erythrocytes, mammalian cells, and Escherichia coli exists predominantly as disordered monomer. Journal of Biological Chemistry 287(19), 15345–15364.Google Scholar
Feng, L. R., Federoff, H. J., Vicini, S. & Maguire-Zeiss, K. A. (2010). Alpha-synuclein mediates alterations in membrane conductance: a potential role for alpha-synuclein oligomers in cell vulnerability. European Journal of Neuroscience 32(1), 10–17.CrossRefGoogle ScholarPubMed
Ferreon, A. C., Gambin, Y., Lemke, E. A. & Deniz, A. A. (2009). Interplay of alpha-synuclein binding and conformational switching probed by single-molecule fluorescence. Proceedings of the National Academy of Sciences United States of America 106(14), 5645–5650.Google Scholar
Fredenburg, R. A., Rospigliosi, C., Meray, R. K., Kessler, J. C., Lashuel, H. A., Eliezer, D. & Lansbury, P. T. Jr. (2007). The impact of the E46K mutation on the properties of alpha-synuclein in its monomeric and oligomeric states. Biochemistry 46(24), 7107–7118.CrossRefGoogle ScholarPubMed
Freeman, D., Cedillos, R., Choyke, S., Lukic, Z., Mcguire, K., Marvin, S., Burrage, A. M., Sudholt, S., Rana, A., O'Connor, C., Wiethoff, C. M. & Campbell, E. M. (2013). Alpha-synuclein induces lysosomal rupture and cathepsin dependent reactive oxygen species following endocytosis. PLoS ONE 8(4), e62143.Google Scholar
Freundt, E. C., Maynard, N., Clancy, E. K., Roy, S., Bousset, L., Sourigues, Y., Covert, M., Melki, R., Kirkegaard, K. & Brahic, M. (2012). Neuron-to-neuron transmission of alpha-synuclein fibrils through axonal transport. Annals of Neurology 72(4), 517–524.CrossRefGoogle ScholarPubMed
Fuchs, J., Tichopad, A., Golub, Y., Munz, M., Schweitzer, K. J., Wolf, B., Berg, D., Mueller, J. C. & Gasser, T. (2008). Genetic variability in the SNCA gene influences alpha-synuclein levels in the blood and brain. FASEB Journal 22(5), 1327–1334.Google Scholar
Fujiwara, H., Hasegawa, M., Dohmae, N., Kawashima, A., Masliah, E., Goldberg, M. S., Shen, J., Takio, K. & Iwatsubo, T. (2002). alpha-Synuclein is phosphorylated in synucleinopathy lesions. Nature Cell Biology 4(2), 160–164.Google Scholar
Funayama, M., Hasegawa, K., Kowa, H., Saito, M., Tsuji, S. & Obata, F. (2002). A new locus for Parkinson's disease (PARK8) maps to chromosome 12p11.2-q13.1. Annals of Neurology 51(3), 296–301.Google Scholar
Georgieva, E. R., Ramlall, T. F., Borbat, P. P., Freed, J. H. & Eliezer, D. (2010). The lipid-binding domain of wild type and mutant alpha-synuclein: compactness and interconversion between the broken and extended helix forms. Journal of Biological Chemistry 285(36), 28261–28274.Google Scholar
Giasson, B. I., Duda, J. E., Murray, I. V., Chen, Q., Souza, J. M., Hurtig, H. I., Ischiropoulos, H., Trojanowski, J. Q. & Lee, V. M. (2000). Oxidative damage linked to neurodegeneration by selective alpha-synuclein nitration in synucleinopathy lesions. Science 290(5493), 985–989.Google Scholar
Giasson, B. I., Murray, I. V., Trojanowski, J. Q. & Lee, V. M. (2001). A hydrophobic stretch of 12 amino acid residues in the middle of alpha-synuclein is essential for filament assembly. Journal of Biological Chemistry 276(4), 2380–2386.Google Scholar
Giehm, L., Lorenzen, N. & Otzen, D. E. (2011a). Assays for alpha-synuclein aggregation. Methods 53(3), 295–305.Google Scholar
Giehm, L. & Otzen, D. E. (2010). Strategies to increase the reproducibility of protein fibrillization in plate reader assays. Analytical Biochemistry 400(2), 270–281.Google Scholar
Giehm, L., Svergun, D. I., Otzen, D. E. & Vestergaard, B. (2011b). Low-resolution structure of a vesicle disrupting α-synuclein oligomer that accumulates during fibrillation. Proceedings of the National Academy of Sciences United States of America 108(8), 3246–3251.Google Scholar
Goers, J., Uversky, V. N. & Fink, A. L. (2003). Polycation-induced oligomerization and accelerated fibrillation of human alpha-synuclein in vitro . Protein Science 12(4), 702–707.CrossRefGoogle ScholarPubMed
Gosavi, N., Lee, H. J., Lee, J. S., Patel, S. & Lee, S. J. (2002). Golgi fragmentation occurs in the cells with prefibrillar alpha-synuclein aggregates and precedes the formation of fibrillar inclusion. Journal of Biological Chemistry 277(50), 48984–48992.CrossRefGoogle ScholarPubMed
Gousset, K., Schiff, E., Langevin, C., Marijanovic, Z., Caputo, A., Browman, D. T., Chenouard, N., De Chaumont, F., Martino, A., Enninga, J., Olivo-Marin, J. C., Mannel, D. & Zurzolo, C. (2009). Prions hijack tunnelling nanotubes for intercellular spread. Nature Cell Biology 11(3), 328–336.Google Scholar
Greten-Harrison, B., Polydoro, M., Morimoto-Tomita, M., Diao, L., Williams, A. M., Nie, E. H., Makani, S., Tian, N., Castillo, P. E., Buchman, V. L. & Chandra, S. S. (2010). alphabetagamma-Synuclein triple knockout mice reveal age-dependent neuronal dysfunction. Proceedings of the National Academy of Sciences United States of America 107(45), 19573–19578.Google Scholar
Groenning, M. (2010). Binding mode of Thioflavin T and other molecular probes in the context of amyloid fibrils-current status. Journal of Chemical Biology 3(1), 1–18.CrossRefGoogle ScholarPubMed
Gurry, T., Ullman, O., Fisher, C. K., Perovic, I., Pochapsky, T. & Stultz, C. M. (2013). The dynamic structure of alpha-synuclein multimers. Journal of the American Chemical Society 135(10), 3865–3872.Google Scholar
Halle, A., Hornung, V., Petzold, G. C., Stewart, C. R., Monks, B. G., Reinheckel, T., Fitzgerald, K. A., Latz, E., Moore, K. J. & Golenbock, D. T. (2008). The NALP3 inflammasome is involved in the innate immune response to amyloid-beta. Nature Immunology 9(8), 857–865.Google Scholar
Hansen, C., Angot, E., Bergstrom, A. L., Steiner, J. A., Pieri, L., Paul, G., Outeiro, T. F., Melki, R., Kallunki, P., Fog, K., Li, J. Y. & Brundin, P. (2011). alpha-Synuclein propagates from mouse brain to grafted dopaminergic neurons and seeds aggregation in cultured human cells. Journal of Clinical Investigation 121(2), 715–725.Google Scholar
Hearps, A. C., Pryor, M. J., Kuusisto, H. V., Rawlinson, S. M., Piller, S. C. & Jans, D. A. (2007). The biarsenical dye Lumio exhibits a reduced ability to specifically detect tetracysteine-containing proteins within live cells. Journal of Fluorescence 17(6), 593–597.Google Scholar
Heise, H., Hoyer, W., Becker, S., Andronesi, O. C., Riedel, D. & Baldus, M. (2005). Molecular-level secondary structure, polymorphism, and dynamics of full-length alpha-synuclein fibrils studied by solid-state NMR. Proceedings of the National Academy of Sciences United States of America 102(44), 15871–15876.Google Scholar
Hervas, R., Oroz, J., Galera-Prat, A., Goni, O., Valbuena, A., Vera, A. M., Gomez-Sicilia, A., Losada-Urzaiz, F., Uversky, V. N., Menendez, M., Laurents, D. V., Bruix, M. & Carrion-Vazquez, M. (2012). Common features at the start of the neurodegeneration cascade. PLoS Biology 10(5), e1001335.Google Scholar
Hirsch, E., Graybiel, A. M. & Agid, Y. A. (1988). Melanized dopaminergic neurons are differentially susceptible to degeneration in Parkinson's disease. Nature 334(6180), 345–348.Google Scholar
Hoyer, W., Antony, T., Cherny, D., Heim, G., Jovin, T. M. & Subramaniam, V. (2002). Dependence of alpha-synuclein aggregate morphology on solution conditions. Journal of Molecular Biology 322(2), 383–393.Google Scholar
Hudson, S. A., Ecroyd, H., Kee, T. W. & Carver, J. A. (2009). The thioflavin T fluorescence assay for amyloid fibril detection can be biased by the presence of exogenous compounds. FEBS Journal 276(20), 5960–5972.Google Scholar
Jao, C. C., Hegde, B. G., Chen, J., Haworth, I. S. & Langen, R. (2008). Structure of membrane-bound alpha-synuclein from site-directed spin labeling and computational refinement. Proceedings of the National Academy of Sciences United States of America 105(50), 19666–19671.Google Scholar
Kaminski Schierle, G. S., Bertoncini, C. W., Chan, F. T., Van Der Goot, A. T., Schwedler, S., Skepper, J., Schlachter, S., Van Ham, T., Esposito, A., Kumita, J. R., Nollen, E. A., Dobson, C. M. & Kaminski, C. F. (2011). A FRET sensor for non-invasive imaging of amyloid formation in vivo . Chemphyschem 12(3), 673–680.Google Scholar
Kang, L., Moriarty, G. M., Woods, L. A., Ashcroft, A. E., Radford, S. E. & Baum, J. (2012). N-terminal acetylation of alpha-synuclein induces increased transient helical propensity and decreased aggregation rates in the intrinsically disordered monomer. Protein Science 21(7), 911–917.Google Scholar
Kasten, M. & Klein, C. (2013). The many faces of alpha-synuclein mutations. Movment Disorders 28(6), 697–701.Google Scholar
Kaylor, J., Bodner, N., Edridge, S., Yamin, G., Hong, D. P. & Fink, A. L. (2005). Characterization of oligomeric intermediates in alpha-synuclein fibrillation: FRET studies of Y125W/Y133F/Y136F alpha-synuclein. Journal of Molecular Biology 353(2), 357–372.CrossRefGoogle ScholarPubMed
Khurana, R., Coleman, C., Ionescu-Zanetti, C., Carter, S. A., Krishna, V., Grover, R. K., Roy, R. & Singh, S. (2005). Mechanism of thioflavin T binding to amyloid fibrils. Journal of Structural Biology 151(3), 229–238.Google Scholar
Khurana, R., Ionescu-Zanetti, C., Pope, M., Li, J., Nielson, L., Ramirez-Alvarado, M., Regan, L., Fink, A. L. & Carter, S. A. (2003). A general model for amyloid fibril assembly based on morphological studies using atomic force microscopy. Biophysics Journal 85(2), 1135–1144.Google Scholar
Khurana, R., Uversky, V. N., Nielsen, L. & Fink, A. L. (2001). Is Congo red an amyloid-specific dye? Journal of Biological Chemistry, 276(25), 22715–22721.Google Scholar
Kiely, A. P., Asi, Y. T., Kara, E., Limousin, P., Ling, H., Lewis, P., Proukakis, C., Quinn, N., Lees, A. J., Hardy, J., Revesz, T., Houlden, H. & Holton, J. L. (2013). alpha-Synucleinopathy associated with G51D SNCA mutation: a link between Parkinson's disease and multiple system atrophy? Acta Neuropathology, 125(5), 753–769.Google Scholar
Kim, C., Ho, D. H., Suk, J. E., You, S., Michael, S., Kang, J., Joong Lee, S., Masliah, E., Hwang, D., Lee, H. J. & Lee, S. J. (2013). Neuron-released oligomeric alpha-synuclein is an endogenous agonist of TLR2 for paracrine activation of microglia. Nature Communications 4, 1562.Google Scholar
Kim, H. Y., Cho, M. K., Kumar, A., Maier, E., Siebenhaar, C., Becker, S., Fernandez, C. O., Lashuel, H. A., Benz, R., Lange, A. & Zweckstetter, M. (2009). Structural properties of pore-forming oligomers of alpha-synuclein. Journal of the American Chemical Society 131(47), 17482–17489.Google Scholar
Kim, H. Y., Cho, M. K., Riedel, D., Fernandez, C. O. & Zweckstetter, M. (2008). Dissociation of amyloid fibrils of alpha-synuclein in supercooled water. Angewandte Chemie International Edition English 47(27), 5046–5048.Google Scholar
Klucken, J., Outeiro, T. F., Nguyen, P., Mclean, P. J. & Hyman, B. T. (2006). Detection of novel intracellular alpha-synuclein oligomeric species by fluorescence lifetime imaging. FASEB Journal 20(12), 2050–2057.Google Scholar
Klucken, J., Shin, Y., Masliah, E., Hyman, B. T. & Mclean, P. J. (2004). Hsp70 Reduces alpha-Synuclein Aggregation and Toxicity. Journal of Biological Chemistry 279(24), 25497–25502.Google Scholar
Kokhan, V. S., Afanasyeva, M. A. & Van'kin, G. I. (2012). alpha-Synuclein knockout mice have cognitive impairments. Behavioural Brain Research 231(1), 226–230.Google Scholar
Kordower, J. H., Chu, Y., Hauser, R. A., Freeman, T. B. & Olanow, C. W. (2008). Lewy body-like pathology in long-term embryonic nigral transplants in Parkinson's disease. Nature Medicine 14(5), 504–506.CrossRefGoogle ScholarPubMed
Kostka, M., Hogen, T., Danzer, K. M., Levin, J., Habeck, M., Wirth, A., Wagner, R., Glabe, C. G., Finger, S., Heinzelmann, U., Garidel, P., Duan, W., Ross, C. A., Kretzschmar, H. & Giese, A. (2008). Single particle characterization of iron-induced pore-forming alpha-synuclein oligomers. Journal of Biological Chemistry 283(16), 10992–11003.Google Scholar
Krebs, M. R., Bromley, E. H. & Donald, A. M. (2005). The binding of thioflavin-T to amyloid fibrils: localisation and implications. Journal of Structural Biology 149(1), 30–37.Google Scholar
Kruger, R., Kuhn, W., Muller, T., Woitalla, D., Graeber, M., Kosel, S., Przuntek, H., Epplen, J. T., Schols, L. & Riess, O. (1998). Ala30Pro mutation in the gene encoding alpha-synuclein in Parkinson's disease. Nature Genetics 18(2), 106–108.CrossRefGoogle ScholarPubMed
Lashuel, H. A. & Lansbury, P. T. Jr. (2006). Are amyloid diseases caused by protein aggregates that mimic bacterial pore-forming toxins? Quartely Review of Biophysics, 39(2), 167–201.Google Scholar
Lashuel, H. A., Petre, B. M., Wall, J., Simon, M., Nowak, R. J., Walz, T. & Lansbury, P. T. Jr. (2002). Alpha-synuclein, especially the Parkinson's disease-associated mutants, forms pore-like annular and tubular protofibrils. Journal of Molecular Biology 322(5), 1089–1102.Google Scholar
Lee, H. J., Choi, C. & Lee, S. J. (2002). Membrane-bound alpha-synuclein has a high aggregation propensity and the ability to seed the aggregation of the cytosolic form. Journal of Biological Chemistry 277(1), 671–678.Google Scholar
Lemkau, L. R., Comellas, G., Kloepper, K. D., Woods, W. S., George, J. M. & Rienstra, C. M. (2012). Mutant protein A30P alpha-synuclein adopts wild-type fibril structure, despite slower fibrillation kinetics. Journal of Biological Chemistry 287(14), 11526–11532.Google Scholar
Lemkau, L. R., Comellas, G., Lee, S. W., Rikardsen, L. K., Woods, W. S., George, J. M. & Rienstra, C. M. (2013). Site-specific perturbations of alpha-synuclein fibril structure by the Parkinson's disease associated mutations A53T and E46K. PLoS ONE 8(3), e49750.Google Scholar
Levine, H. III. (1993). Thioflavine T interaction with synthetic Alzheimer's disease beta-amyloid peptides: detection of amyloid aggregation in solution. Protein Science 2(3), 404–410.Google Scholar
Li, J., Uversky, V. N. & Fink, A. L. (2001). Effect of familial Parkinson's disease point mutations A30P and A53T on the structural properties, aggregation, and fibrillation of human alpha-synuclein. Biochemistry 40(38), 11604–11613.Google Scholar
Li, J. Y., Englund, E., Holton, J. L., Soulet, D., Hagell, P., Lees, A. J., Lashley, T., Quinn, N. P., Rehncrona, S., Bjorklund, A., Widner, H., Revesz, T., Lindvall, O. & Brundin, P. (2008). Lewy bodies in grafted neurons in subjects with Parkinson's disease suggest host-to-graft disease propagation. Nature Medicine 14(5), 501–503.Google Scholar
Liu, I. H., Uversky, V. N., Munishkina, L. A., Fink, A. L., Halfter, W. & Cole, G. J. (2005). Agrin binds alpha-synuclein and modulates alpha-synuclein fibrillation. Glycobiology 15(12), 1320–1331.Google Scholar
Liu, S., Ninan, I., Antonova, I., Battaglia, F., Trinchese, F., Narasanna, A., Kolodilov, N., Dauer, W., Hawkins, R. D. & Arancio, O. (2004). alpha-Synuclein produces a long-lasting increase in neurotransmitter release. EMBO Journal 23(22), 4506–4516.Google Scholar
Lowe, R., Pountney, D. L., Jensen, P. H., Gai, W. P. & Voelcker, N. H. (2004). Calcium(II) selectively induces alpha-synuclein annular oligomers via interaction with the C-terminal domain. Protein Science 13(12), 3245–3252.Google Scholar
Luk, K. C., Hyde, E. G., Trojanowski, J. Q. & Lee, V. M. (2007). Sensitive fluorescence polarization technique for rapid screening of alpha-synuclein oligomerization/fibrillization inhibitors. Biochemistry 46(44), 12522–12529.Google Scholar
Luk, K. C., Kehm, V., Carroll, J., Zhang, B., O'BRIEN, P., Trojanowski, J. Q. & Lee, V. M. (2012). Pathological alpha-synuclein transmission initiates Parkinson-like neurodegeneration in nontransgenic mice. Science 338(6109), 949–953.Google Scholar
Luk, K. C., Song, C., O'Brien, P., Stieber, A., Branch, J. R., Brunden, K. R., Trojanowski, J. Q. & Lee, V. M. (2009). Exogenous alpha-synuclein fibrils seed the formation of Lewy body-like intracellular inclusions in cultured cells. Proceedings of the National Academy of Sciences United States of America 106(47), 20051–20056.Google Scholar
Maguire-Zeiss, K. A. & Federoff, H. J. (2010). Future directions for immune modulation in neurodegenerative disorders: focus on Parkinson's disease. Journal of Neural Transmission 117(8), 1019–1025.Google Scholar
Mak, S. K., Mccormack, A. L., Manning-Bog, A. B., Cuervo, A. M. & Di Monte, D. A. (2010). Lysosomal degradation of alpha-synuclein in vivo . Journal of Biological Chemistry 285(18), 13621–13629.Google Scholar
Mbefo, M. K., Paleologou, K. E., Boucharaba, A., Oueslati, A., Schell, H., Fournier, M., Olschewski, D., Yin, G., Zweckstetter, M., Masliah, E., Kahle, P. J., Hirling, H. & Lashuel, H. A. (2010). Phosphorylation of synucleins by members of the Polo-like kinase family. Journal of Biological Chemistry 285(4), 2807–2822.CrossRefGoogle ScholarPubMed
Mcclendon, S., Rospigliosi, C. C. & Eliezer, D. (2009). Charge neutralization and collapse of the C-terminal tail of alpha-synuclein at low pH. Protein Science 18(7), 1531–1540.Google Scholar
Mclean, P. J., Kawamata, H. & Hyman, B. T. (2001). Alpha-synuclein-enhanced green fluorescent protein fusion proteins form proteasome sensitive inclusions in primary neurons. Neuroscience 104(3), 901–912.Google Scholar
Middleton, E. R. & Rhoades, E. (2010). Effects of curvature and composition on alpha-synuclein binding to lipid vesicles. Biophysics Journal 99(7), 2279–2288.Google Scholar
Miller, L. M., Bourassa, M. W. & Smith, R. J. (2013). FTIR spectroscopic imaging of protein aggregation in living cells. Biochimica et Biophysica Acta 1828(10), 2339–2346.Google Scholar
Morris, A. M., Watzky, M. A. & Finke, R. G. (2009). Protein aggregation kinetics, mechanism, and curve-fitting: a review of the literature. Biochimica et Biophysica Acta 1794(3), 375–397.Google Scholar
Mosharov, E. V., Staal, R. G., Bove, J., Prou, D., Hananiya, A., Markov, D., Poulsen, N., Larsen, K. E., Moore, C. M., Troyer, M. D., Edwards, R. H., Przedborski, S. & Sulzer, D. (2006). Alpha-synuclein overexpression increases cytosolic catecholamine concentration. Journal of Neuroscience 26(36), 9304–9311.Google Scholar
Nakamura, K., Nemani, V. M., Azarbal, F., Skibinski, G., Levy, J. M., Egami, K., Munishkina, L., Zhang, J., Gardner, B., Wakabayashi, J., Sesaki, H., Cheng, Y., Finkbeiner, S., Nussbaum, R. L., Masliah, E. & Edwards, R. H. (2011). Direct membrane association drives mitochondrial fission by the Parkinson disease-associated protein alpha-synuclein. Journal of Biological Chemistry 286(23), 20710–20726.CrossRefGoogle ScholarPubMed
Nakamura, K., Nemani, V. M., Wallender, E. K., Kaehlcke, K., Ott, M. & Edwards, R. H. (2008). Optical reporters for the conformation of alpha-synuclein reveal a specific interaction with mitochondria. Journal of Neuroscience 28(47), 12305–12317.Google Scholar
Nasstrom, T., Fagerqvist, T., Barbu, M., Karlsson, M., Nikolajeff, F., Kasrayan, A., Ekberg, M., Lannfelt, L., Ingelsson, M. & Bergstrom, J. (2011). The lipid peroxidation products 4-oxo-2-nonenal and 4-hydroxy-2-nonenal promote the formation of alpha-synuclein oligomers with distinct biochemical, morphological, and functional properties. Free Radical Biology and Medicine 50(3), 428–437.Google Scholar
Nath, S., Meuvis, J., Hendrix, J., Carl, S. A. & Engelborghs, Y. (2010). Early aggregation steps in alpha-synuclein as measured by FCS and FRET: evidence for a contagious conformational change. Biophysics Journal 98(7), 1302–1311.Google Scholar
Necula, M., Chirita, C. N. & Kuret, J. (2003). Rapid anionic micelle-mediated alpha-synuclein fibrillization in vitro . Journal of Biological Chemistry 278(47), 46674–46680.Google Scholar
Nemani, V. M., Lu, W., Berge, V., Nakamura, K., Onoa, B., Lee, M. K., Chaudhry, F. A., Nicoll, R. A. & Edwards, R. H. (2010). Increased expression of alpha-synuclein reduces neurotransmitter release by inhibiting synaptic vesicle reclustering after endocytosis. Neuron 65(1), 66–79.Google Scholar
Nonaka, T., Watanabe, S. T., Iwatsubo, T. & Hasegawa, M. (2010). Seeded aggregation and toxicity of {alpha}-synuclein and tau: cellular models of neurodegenerative diseases. Journal of Biological Chemistry 285(45), 34885–34898.Google Scholar
Olzscha, H., Schermann, S. M., Woerner, A. C., Pinkert, S., Hecht, M. H., Tartaglia, G. G., Vendruscolo, M., Hayer-Hartl, M., Hartl, F. U. & Vabulas, R. M. (2011). Amyloid-like aggregates sequester numerous metastable proteins with essential cellular functions. Cell 144(1), 67–78.Google Scholar
Orte, A., Birkett, N. R., Clarke, R. W., Devlin, G. L., Dobson, C. M. & Klenerman, D. (2008). Direct characterization of amyloidogenic oligomers by single-molecule fluorescence. Proceedings of the National Academy of Sciences United States of America 105(38), 14424–14429.Google Scholar
Outeiro, T. F., Putcha, P., Tetzlaff, J. E., Spoelgen, R., Koker, M., Carvalho, F., Hyman, B. T. & Mclean, P. J. (2008). Formation of toxic oligomeric alpha-synuclein species in living cells. PLoS ONE 3(4), e1867.CrossRefGoogle ScholarPubMed
Paleologou, K. E., Oueslati, A., Shakked, G., Rospigliosi, C. C., Kim, H. Y., Lamberto, G. R., Fernandez, C. O., Schmid, A., Chegini, F., Gai, W. P., Chiappe, D., Moniatte, M., Schneider, B. L., Aebischer, P., Eliezer, D., Zweckstetter, M., Masliah, E. & Lashuel, H. A. (2010). Phosphorylation at S87 is enhanced in synucleinopathies, inhibits alpha-synuclein oligomerization, and influences synuclein-membrane interactions. Journal of Neuroscience 30(9), 3184–3198.Google Scholar
Paleologou, K. E., Schmid, A. W., Rospigliosi, C. C., Kim, H. Y., Lamberto, G. R., Fredenburg, R. A., Lansbury, P. T. Jr., Fernandez, C. O., Eliezer, D., Zweckstetter, M. & Lashuel, H. A. (2008). Phosphorylation at Ser-129 but not the phosphomimics S129E/D inhibits the fibrillation of alpha-synuclein. Journal of Biological Chemistry 283(24), 16895–16905.Google Scholar
Palomaki, J., Valimaki, E., Sund, J., Vippola, M., Clausen, P. A., Jensen, K. A., Savolainen, K., Matikainen, S. & Alenius, H. (2011). Long, needle-like carbon nanotubes and asbestos activate the NLRP3 inflammasome through a similar mechanism. ACS Nano 5(9), 6861–6870.Google Scholar
Pinotsi, D., Buell, A. K., Dobson, C. M., Kaminski Schierle, G. S. & Kaminski, C. F. (2013). A label-free, quantitative assay of amyloid fibril growth based on intrinsic fluorescence. ChemBioChem 14(7), 846–850.Google Scholar
Pivato, M., De Franceschi, G., Tosatto, L., Frare, E., Kumar, D., Aioanei, D., Brucale, M., Tessari, I., Bisaglia, M., Samori, B., De Laureto, P. P. & Bubacco, L. (2012). Covalent alpha-synuclein dimers: chemico-physical and aggregation properties. PLoS ONE 7(12), e50027.Google Scholar
Plotegher, N. & Civiero, L. (2012). Neuronal autophagy, alpha-synuclein clearance, and LRRK2 regulation: a lost equilibrium in parkinsonian brain. Journal of Neuroscience 32(43), 14851–14853.Google Scholar
Polymenidou, M. & Cleveland, D. W. (2012). Prion-like spread of protein aggregates in neurodegeneration. Journal of Experimental Medicine 209(5), 889–893.Google Scholar
Polymeropoulos, M. H., Lavedan, C., Leroy, E., Ide, S. E., Dehejia, A., Dutra, A., Pike, B., Root, H., Rubenstein, J., Boyer, R., Stenroos, E. S., Chandrasekharappa, S., Athanassiadou, A., Papapetropoulos, T., Johnson, W. G., Lazzarini, A. M., Duvoisin, R. C., Di Iorio, G., Golbe, L. I. & Nussbaum, R. L. (1997). Mutation in the alpha-synuclein gene identified in families with Parkinson's disease. Science 276(5321), 2045–2047.Google Scholar
Pountney, D. L., Lowe, R., Quilty, M., Vickers, J. C., Voelcker, N. H. & Gai, W. P. (2004). Annular alpha-synuclein species from purified multiple system atrophy inclusions. Journal of Neurochemistry 90(2), 502–512.Google Scholar
Pronchik, J., He, X., Giurleo, J. T. & Talaga, D. S. (2010). In vitro formation of amyloid from alpha-synuclein is dominated by reactions at hydrophobic interfaces. Journal of the American Chemical Society, 132(28), 9797–9803.Google Scholar
Proukakis, C., Dudzik, C. G., Brier, T., Mackay, D. S., Cooper, J. M., Millhauser, G. L., Houlden, H. & Schapira, A. H. (2013). A novel alpha-synuclein missense mutation in Parkinson disease. Neurology 80(11), 1062–1064.Google Scholar
Qin, Z., Hu, D., Han, S., Hong, D. P. & Fink, A. L. (2007a). Role of different regions of alpha-synuclein in the assembly of fibrils. Biochemistry 46(46), 13322–13330.Google Scholar
Qin, Z., Hu, D., Han, S., Reaney, S. H., Di Monte, D. A. & Fink, A. L. (2007b). Effect of 4-hydroxy-2-nonenal modification on alpha-synuclein aggregation. Journal of Biological Chemistry 282(8), 5862–5870.Google Scholar
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. Proceedings of the National Academy of Sciences United States of America 102(30), 10427–10432.Google Scholar
Rekas, A., Knott, R. B., Sokolova, A., Barnham, K. J., Perez, K. A., Masters, C. L., Drew, S. C., Cappai, R., Curtain, C. C. & Pham, C. L. (2010). The structure of dopamine induced alpha-synuclein oligomers. European Biophysics Journal 39(10), 1407–1419.CrossRefGoogle ScholarPubMed
Reynolds, N. P., Soragni, A., Rabe, M., Verdes, D., Liverani, E., Handschin, S., Riek, R. & Seeger, S. (2011). Mechanism of membrane interaction and disruption by alpha-synuclein. Journal of the American Chemical Society 133(48), 19366–19375.Google Scholar
Ries, J., Udayar, V., Soragni, A., Hornemann, S., Nilsson, K. P., Riek, R., Hock, C., Ewers, H., Aguzzi, A. A. & Rajendran, L. (2013). Superresolution imaging of amyloid fibrils with binding-activated probes. ACS Chemical Neuroscience 4(7), 1057–1061.Google Scholar
Roberti, M. J., Bertoncini, C. W., Klement, R., Jares-Erijman, E. A. & Jovin, T. M. (2007). Fluorescence imaging of amyloid formation in living cells by a functional, tetracysteine-tagged alpha-synuclein. Nature Methods 4(4), 345–351.Google Scholar
Roberti, M. J., Folling, J., Celej, M. S., Bossi, M., Jovin, T. M. & Jares-Erijman, E. A. (2012). Imaging nanometer-sized alpha-synuclein aggregates by superresolution fluorescence localization microscopy. Biophysics Journal 102(7), 1598–1607.Google Scholar
Roberti, M. J., Jovin, T. M. & Jares-Erijman, E. (2011). Confocal fluorescence anisotropy and FRAP imaging of alpha-synuclein amyloid aggregates in living cells. PLoS ONE 6(8), e23338.Google Scholar
Roostaee, A., Beaudoin, S., Staskevicius, A. & Roucou, X. (2013). Aggregation and neurotoxicity of recombinant alpha-synuclein aggregates initiated by dimerization. Molecular Neurodegeneration 8, 5.Google Scholar
Ross, C. A. & Poirier, M. A. (2004). Protein aggregation and neurodegenerative disease. Nature Medicine 10(Suppl), S10–S17.Google Scholar
Rustom, A., Saffrich, R., Markovic, I., Walther, P. & Gerdes, H. H. (2004). Nanotubular highways for intercellular organelle transport. Science 303(5660), 1007–1010.Google Scholar
Sandal, M., Valle, F., Tessari, I., Mammi, S., Bergantino, E., Musiani, F., Brucale, M., Bubacco, L. & Samori, B. (2008). Conformational equilibria in monomeric alpha-synuclein at the single-molecule level. PLoS Biology 6(1), e6.Google Scholar
Schmidt, F., Levin, J., Kamp, F., Kretzschmar, H., Giese, A. & Botzel, K. (2012). Single-channel electrophysiology reveals a distinct and uniform pore complex formed by alpha-synuclein oligomers in lipid membranes. PLoS ONE 7(8), e42545.Google Scholar
Serpell, L. C., Berriman, J., Jakes, R., Goedert, M. & Crowther, R. A. (2000). Fiber diffraction of synthetic alpha-synuclein filaments shows amyloid-like cross-beta conformation. Proceedings of the National Academy of Sciences United States of America 97(9), 4897–4902.Google Scholar
Shirakashi, Y., Kawamoto, Y., Tomimoto, H., Takahashi, R. & Ihara, M. (2006). alpha-Synuclein is colocalized with 14–3–3 and synphilin-1 in A53T transgenic mice. Acta Neuropathology 112(6), 681–689.CrossRefGoogle ScholarPubMed
Sievers, S. A., Karanicolas, J., Chang, H. W., Zhao, A., Jiang, L., Zirafi, O., Stevens, J. T., Munch, J., Baker, D. & Eisenberg, D. (2011). Structure-based design of non-natural amino-acid inhibitors of amyloid fibril formation. Nature 475(7354), 96–100.Google Scholar
Singleton, A. B., Farrer, M., Johnson, J., Singleton, A., Hague, S., Kachergus, J., Hulihan, M., Peuralinna, T., Dutra, A., Nussbaum, R., Lincoln, S., Crawley, A., Hanson, M., Maraganore, D., Adler, C., Cookson, M. R., Muenter, M., Baptista, M., Miller, D., Blancato, J., Hardy, J. & Gwinn-Hardy, K. (2003). alpha-Synuclein locus triplication causes Parkinson's disease. Science 302(5646), 841.Google Scholar
Smith, W. W., Jiang, H., Pei, Z., Tanaka, Y., Morita, H., Sawa, A., Dawson, V. L., Dawson, T. M. & Ross, C. A. (2005). Endoplasmic reticulum stress and mitochondrial cell death pathways mediate A53T mutant alpha-synuclein-induced toxicity. Human Molecular Genetics 14(24), 3801–3811.Google Scholar
Sousa, V. L., Bellani, S., Giannandrea, M., Yousuf, M., Valtorta, F., Meldolesi, J. & Chieregatti, E. (2009). {alpha}-synuclein and its A30P mutant affect actin cytoskeletal structure and dynamics. Molecular Biology of the Cell 20(16), 3725–3739.Google Scholar
Spillantini, M. G., Crowther, R. A., Jakes, R., Hasegawa, M. & Goedert, M. (1998). alpha-Synuclein in filamentous inclusions of Lewy bodies from Parkinson's disease and dementia with Lewy bodies. Proceedings of the National Academy of Sciences United States of America 95(11), 6469–6473.Google Scholar
Spillantini, M. G., Schmidt, M. L., Lee, V. M., Trojanowski, J. Q., Jakes, R. & Goedert, M. (1997). Alpha-synuclein in Lewy bodies. Nature 388(6645), 839–840.Google Scholar
Steiner, J. A., Angot, E. & Brundin, P. (2011). A deadly spread: cellular mechanisms of alpha-synuclein transfer. Cell Death and Differentiation 18(9), 1425–1433.Google Scholar
Stroffekova, K., Proenza, C. & Beam, K. G. (2001). The protein-labeling reagent FLASH-EDT2 binds not only to CCXXCC motifs but also non-specifically to endogenous cysteine-rich proteins. Pflugers Arch 442(6), 859–866.Google Scholar
Suk, J. E., Lokappa, S. B. & Ulmer, T. S. (2010). The clustering and spatial arrangement of beta-sheet sequence, but not order, govern alpha-synuclein fibrillogenesis. Biochemistry 49(7), 1533–1540.Google Scholar
Sulatskaya, A. I., Kuznetsova, I. M. & Turoverov, K. K. (2011). Interaction of thioflavin T with amyloid fibrils: stoichiometry and affinity of dye binding, absorption spectra of bound dye. Journal of Physical Chemistry B 115(39), 11519–11524.Google Scholar
Takeda, A., Mallory, M., Sundsmo, M., Honer, W., Hansen, L. & Masliah, E. (1998). Abnormal accumulation of NACP/alpha-synuclein in neurodegenerative disorders. American Journal of Pathology 152(2), 367–372.Google Scholar
Tanaka, Y., Engelender, S., Igarashi, S., Rao, R. K., Wanner, T., Tanzi, R. E., Sawa, A., Dawson, V. L., Dawson, T. M. & Ross, C. A. (2001). Inducible expression of mutant alpha-synuclein decreases proteasome activity and increases sensitivity to mitochondria-dependent apoptosis. Human Molecular Genetics 10(9), 919–926.Google Scholar
Taschenberger, G., Toloe, J., Tereshchenko, J., Akerboom, J., Wales, P., Benz, R., Becker, S., Outeiro, T., Looger, L., Bahr, M., Zweckstetter, M. & Kugler, S. (2013). β-synuclein aggregates and induces neurodegeneration in dopaminergic neurons. Annals of Neurology 74(1), 109–118.Google Scholar
Thirunavukkuarasu, S., Jares-Erijman, E. A. & Jovin, T. M. (2008). Multiparametric fluorescence detection of early stages in the amyloid protein aggregation of pyrene-labeled alpha-synuclein. Journal of Molecular Biology 378(5), 1064–1073.Google Scholar
Tosatto, L., Andrighetti, A. O., Plotegher, N., Antonini, V., Tessari, I., Ricci, L., Bubacco, L. & Dalla Serra, M. (2012). Alpha-synuclein pore forming activity upon membrane association. Biochimica et Biophysica Acta 1818(11), 2876–2883.Google Scholar
Trexler, A. J. & Rhoades, E. (2009). Alpha-synuclein binds large unilamellar vesicles as an extended helix. Biochemistry 48(11), 2304–2306.Google Scholar
Trexler, A. J. & Rhoades, E. (2010). Single molecule characterization of alpha-synuclein in aggregation-prone states. Biophysics Journal 99(9), 3048–3055.Google Scholar
Trexler, A. J. & Rhoades, E. (2012). N-Terminal acetylation is critical for forming alpha-helical oligomer of alpha-synuclein. Protein Science 21(5), 601–605.Google Scholar
Trojanowski, J. Q. & Lee, V. M. (2003). Parkinson's disease and related alpha-synucleinopathies are brain amyloidoses. Annals of the New York Academy of Sciences 991, 107–110.Google Scholar
Tsigelny, I. F., Bar-On, P., Sharikov, Y., Crews, L., Hashimoto, M., Miller, M. A., Keller, S. H., Platoshyn, O., Yuan, J. X. & Masliah, E. (2007). Dynamics of alpha-synuclein aggregation and inhibition of pore-like oligomer development by beta-synuclein. FEBS Journal 274(7), 1862–1877.Google Scholar
Ulmer, T. S., Bax, A., Cole, N. B. & Nussbaum, R. L. (2005). Structure and dynamics of micelle-bound human alpha-synuclein. Journal of Biological Chemistry 280(10), 9595–9603.CrossRefGoogle ScholarPubMed
Uversky, V. N., Yamin, G., Souillac, P. O., Goers, J., Glaser, C. B. & Fink, A. L. (2002). Methionine oxidation inhibits fibrillation of human alpha-synuclein in vitro . FEBS Letter 517(1–3), 239–244.Google Scholar
Van Ham, T. J., Esposito, A., Kumita, J. R., Hsu, S. T., Kaminski Schierle, G. S., Kaminski, C. F., Dobson, C. M., Nollen, E. A. & Bertoncini, C. W. (2010). Towards multiparametric fluorescent imaging of amyloid formation: studies of a YFP model of alpha-synuclein aggregation. Journal of Molecular Biology 395(3), 627–642.Google Scholar
Van Raaij, M. E., Segers-Nolten, I. M. & Subramaniam, V. (2006). Quantitative morphological analysis reveals ultrastructural diversity of amyloid fibrils from alpha-synuclein mutants. Biophysics Journal 91(11), L96–L98.Google Scholar
Van Raaij, M. E., Van Gestel, J., Segers-Nolten, I. M., De Leeuw, S. W. & Subramaniam, V. (2008). Concentration dependence of alpha-synuclein fibril length assessed by quantitative atomic force microscopy and statistical-mechanical theory. Biophysics Journal 95(10), 4871–4878.Google Scholar
Van Rooijen, B. D., Claessens, M. M. & Subramaniam, V. (2009a). Lipid bilayer disruption by oligomeric alpha-synuclein depends on bilayer charge and accessibility of the hydrophobic core. Biochimica et Biophysica Acta 1788(6), 1271–1278.Google Scholar
Van Rooijen, B. D., Claessens, M. M. & Subramaniam, V. (2010). Membrane Permeabilization by Oligomeric alpha-Synuclein: In Search of the Mechanism. PLoS ONE, 5(12), e14292.Google Scholar
Van Rooijen, B. D., Van Leijenhorst-Groener, K. A., Claessens, M. M. & Subramaniam, V. (2009b). Tryptophan fluorescence reveals structural features of alpha-synuclein oligomers. Journal of Molecular Biology 394(5), 826–833.Google Scholar
Vilar, M., Chou, H. T., Luhrs, T., Maji, S. K., Riek-Loher, D., Verel, R., Manning, G., Stahlberg, H. & Riek, R. (2008). The fold of alpha-synuclein fibrils. Proceedings of the National Academy of Sciences United States of America 105(25), 8637–8642.Google Scholar
Volles, M. J. & Lansbury, P. T. Jr. (2002). Vesicle permeabilization by protofibrillar alpha-synuclein is sensitive to Parkinson's disease-linked mutations and occurs by a pore-like mechanism. Biochemistry 41(14), 4595–4602.Google Scholar
Volpicelli-Daley, L. A., Luk, K. C., Patel, T. P., Tanik, S. A., Riddle, D. M., Stieber, A., Meaney, D. F., Trojanowski, J. Q. & Lee, V. M. (2011). Exogenous alpha-synuclein fibrils induce Lewy body pathology leading to synaptic dysfunction and neuron death. Neuron 72(1), 57–71.Google Scholar
Wang, W., Perovic, I., Chittuluru, J., Kaganovich, A., Nguyen, L. T., Liao, J., Auclair, J. R., Johnson, D., Landeru, A., Simorellis, A. K., Ju, S., Cookson, M. R., Asturias, F. J., Agar, J. N., Webb, B. N., Kang, C., Ringe, D., Petsko, G. A., Pochapsky, T. C. & Hoang, Q. Q. (2011). A soluble alpha-synuclein construct forms a dynamic tetramer. Proceedings of the National Academy of Sciences United States of America 108(43), 17797–17802.Google Scholar
Waxman, E. A. & Giasson, B. I. (2010). A novel, high-efficiency cellular model of fibrillar alpha-synuclein inclusions and the examination of mutations that inhibit amyloid formation. Journal of Neurochemistry 113(2), 374–388.Google Scholar
Weinreb, P. H., Zhen, W., Poon, A. W., Conway, K. A. & Lansbury, P. T. Jr. (1996). NACP, a protein implicated in Alzheimer's disease and learning, is natively unfolded. Biochemistry 35(43), 13709–13715.Google Scholar
Winner, B., Jappelli, R., Maji, S. K., Desplats, P. A., Boyer, L., Aigner, S., Hetzer, C., Loher, T., Vilar, M., Campioni, S., Tzitzilonis, C., Soragni, A., Jessberger, S., Mira, H., Consiglio, A., Pham, E., Masliah, E., Gage, F. H. & Riek, R. (2011). In vivo demonstration that alpha-synuclein oligomers are toxic. Proceedings of the National Academy of Sciences United States of America, 108(10), 4194–4199.Google Scholar
Wolfe, L. S., Calabrese, M. F., Nath, A., Blaho, D. V., Miranker, A. D. & Xiong, Y. (2010). Protein-induced photophysical changes to the amyloid indicator dye thioflavin T. Proceedings of the National Academy of Sciences United States of America 107(39), 16863–16868.Google Scholar
Wood, S. J., Wypych, J., Steavenson, S., Louis, J. C., Citron, M. & Biere, A. L. (1999). alpha-synuclein fibrillogenesis is nucleation-dependent. Implications for the pathogenesis of Parkinson's disease. Journal of Biological Chemistry 274(28), 19509–19512.Google Scholar
Wu, K. P. & Baum, J. (2010). Detection of transient interchain interactions in the intrinsically disordered protein alpha-synuclein by NMR paramagnetic relaxation enhancement. Journal of the American Chemical Society 132(16), 5546–5547.Google Scholar
Wu, K. P., Weinstock, D. S., Narayanan, C., Levy, R. M. & Baum, J. (2009). Structural reorganization of alpha-synuclein at low pH observed by NMR and REMD simulations. Journal of Molecular Biology 391(4), 784–796.Google Scholar
Xia, Q., Liao, L., Cheng, D., Duong, D. M., Gearing, M., Lah, J. J., Levey, A. I. & Peng, J. (2008). Proteomic identification of novel proteins associated with Lewy bodies. Frontiers in Bioscience 13, 3850–3856.Google Scholar
Xu, J., Kao, S. Y., Lee, F. J., Song, W., Jin, L. W. & Yankner, B. A. (2002). Dopamine-dependent neurotoxicity of alpha-synuclein: a mechanism for selective neurodegeneration in Parkinson disease. Nature Medicine 8(6), 600–606.Google Scholar
Yamin, G., Munishkina, L. A., Karymov, M. A., Lyubchenko, Y. L., Uversky, V. N. & Fink, A. L. (2005). Forcing nonamyloidogenic beta-synuclein to fibrillate. Biochemistry 44(25), 9096–9107.Google Scholar
Yamin, G., Uversky, V. N. & Fink, A. L. (2003). Nitration inhibits fibrillation of human alpha-synuclein in vitro by formation of soluble oligomers. FEBS Letter 542(1–3), 147–152.Google Scholar
Yap, T. L., Pfefferkorn, C. M. & Lee, J. C. (2011). Residue-specific fluorescent probes of alpha-synuclein: detection of early events at the N- and C-termini during fibril assembly. Biochemistry 50(12), 1963–1965.Google Scholar
Yoritaka, A., Hattori, N., Uchida, K., Tanaka, M., Stadtman, E. R. & Mizuno, Y. (1996). Immunohistochemical detection of 4-hydroxynonenal protein adducts in Parkinson disease. Proceedings of the National Academy of Sciences United States of America 93(7), 2696–2701.Google Scholar
Yushchenko, D. A., Fauerbach, J. A., Thirunavukkuarasu, S., Jares-Erijman, E. A. & Jovin, T. M. (2010). Fluorescent ratiometric MFC probe sensitive to early stages of alpha-synuclein aggregation. Journal of the American Chemical Society 132(23), 7860–7861.Google Scholar
Zakharov, S. D., Hulleman, J. D., Dutseva, E. A., Antonenko, Y. N., Rochet, J. C. & Cramer, W. A. (2007). Helical alpha-synuclein forms highly conductive ion channels. Biochemistry 46(50), 14369–14379.Google Scholar
Zarranz, J. J., Alegre, J., Gomez-Esteban, J. C., Lezcano, E., Ros, R., Ampuero, I., Vidal, L., Hoenicka, J., Rodriguez, O., Atares, B., Llorens, V., Gomez Tortosa, E., Del Ser, T., Munoz, D. G. & De Yebenes, J. G. (2004). The new mutation, E46K, of alpha-synuclein causes Parkinson and Lewy body dementia. Annals of Neurology 55(2), 164–173.Google Scholar
Zibaee, S., Jakes, R., Fraser, G., Serpell, L. C., Crowther, R. A. & Goedert, M. (2007). Sequence determinants for amyloid fibrillogenesis of human alpha-synuclein. Journal of Molecular Biology 374(2), 454–464.Google Scholar
Zijlstra, N., Blum, C., Segers-Nolten, I. M., Claessens, M. M. & Subramaniam, V. (2012). Molecular composition of sub-stoichiometrically labeled alpha-synuclein oligomers determined by single-molecule photobleaching. Angewandte Chemie International Edition English 51(35), 8821–8824.Google Scholar
Zimprich, A., Benet-Pages, A., Struhal, W., Graf, E., Eck, S. H., Offman, M. N., Haubenberger, D., Spielberger, S., Schulte, E. C., Lichtner, P., Rossle, S. C., Klopp, N., Wolf, E., Seppi, K., Pirker, W., Presslauer, S., Mollenhauer, B., Katzenschlager, R., Foki, T., Hotzy, C., Reinthaler, E., Harutyunyan, A., Kralovics, R., Peters, A., Zimprich, F., Brucke, T., Poewe, W., Auff, E., Trenkwalder, C., Rost, B., Ransmayr, G., Winkelmann, J., Meitinger, T. & Strom, T. M. (2011). A mutation in VPS35, encoding a subunit of the retromer complex, causes late-onset Parkinson disease. American Journal of Human Genetics 89(1), 168–175.Google Scholar