Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Science 9 November 2001:
Vol. 294. no. 5545, pp. 1346 - 1349
DOI: 10.1126/science.1063522
Prev | Table of Contents | Next

Reports

Kinetic Stabilization of the alpha -Synuclein Protofibril by a Dopamine-alpha -Synuclein Adduct

Kelly A. Conway,* Jean-Christophe Rochet,* Robert M. Bieganski, Peter T. Lansbury Jr.dagger

The substantia nigra in Parkinson's disease (PD) is depleted of dopaminergic neurons and contains fibrillar Lewy bodies comprising primarily alpha -synuclein. We screened a library to identify drug-like molecules to probe the relation between neurodegeneration and alpha -synuclein fibrilization. All but one of 15 fibril inhibitors were catecholamines related to dopamine. The inhibitory activity of dopamine depended on its oxidative ligation to alpha -synuclein and was selective for the protofibril-to-fibril conversion, causing accumulation of the alpha -synuclein protofibril. Adduct formation provides an explanation for the dopaminergic selectivity of alpha -synuclein-associated neurotoxicity in PD and has implications for current and future PD therapeutic and diagnostic strategies.

Center for Neurologic Diseases, Brigham and Women's Hospital, Department of Neurology, Harvard Medical School, 65 Landsdowne Street, Cambridge, MA 02139, USA.
*   These authors contributed equally to this work.

dagger    To whom correspondence should be addressed. E-mail: plansbury{at}rics.bwh.harvard.edu

Read the Full Text


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Peroxidase Mechanism of Lipid-dependent Cross-linking of Synuclein with Cytochrome c: PROTECTION AGAINST APOPTOSIS VERSUS DELAYED OXIDATIVE STRESS IN PARKINSON DISEASE.
H. Bayir, A. A. Kapralov, J. Jiang, Z. Huang, Y. Y. Tyurina, V. A. Tyurin, Q. Zhao, N. A. Belikova, I. I. Vlasova, A. Maeda, et al. (2009)
J. Biol. Chem. 284, 15951-15969
   Abstract »    Full Text »    PDF »
Protein Electrophile-Binding Motifs: Lysine-Rich Proteins Are Preferential Targets of Quinones.
M. T. Labenski, A. A. Fisher, H.-H. Lo, T. J. Monks, and S. S. Lau (2009)
Drug Metab. Dispos. 37, 1211-1218
   Abstract »    Full Text »    PDF »
Copper{middle dot}Dopamine Complex Induces Mitochondrial Autophagy Preceding Caspase-independent Apoptotic Cell Death.
I. Paris, C. Perez-Pastene, E. Couve, P. Caviedes, S. LeDoux, and J. Segura-Aguilar (2009)
J. Biol. Chem. 284, 13306-13315
   Abstract »    Full Text »    PDF »
Detecting Morphologically Distinct Oligomeric Forms of {alpha}-Synuclein.
S. Emadi, S. Kasturirangan, M. S. Wang, P. Schulz, and M. R. Sierks (2009)
J. Biol. Chem. 284, 11048-11058
   Abstract »    Full Text »    PDF »
Structural insights on physiological functions and pathological effects of {alpha}-synuclein.
M. Bisaglia, S. Mammi, and L. Bubacco (2009)
FASEB J 23, 329-340
   Abstract »    Full Text »    PDF »
Effects of Grape Seed-derived Polyphenols on Amyloid {beta}-Protein Self-assembly and Cytotoxicity.
K. Ono, M. M. Condron, L. Ho, J. Wang, W. Zhao, G. M. Pasinetti, and D. B. Teplow (2008)
J. Biol. Chem. 283, 32176-32187
   Abstract »    Full Text »    PDF »
Unregulated Cytosolic Dopamine Causes Neurodegeneration Associated with Oxidative Stress in Mice.
L. Chen, Y. Ding, B. Cagniard, A. D. Van Laar, A. Mortimer, W. Chi, T. G. Hastings, U. J. Kang, and X. Zhuang (2008)
J. Neurosci. 28, 425-433
   Abstract »    Full Text »    PDF »
Cellular Oligomerization of {alpha}-Synuclein Is Determined by the Interaction of Oxidized Catechols with a C-terminal Sequence.
J. R. Mazzulli, M. Armakola, M. Dumoulin, I. Parastatidis, and H. Ischiropoulos (2007)
J. Biol. Chem. 282, 31621-31630
   Abstract »    Full Text »    PDF »
Anti-Abeta1 11 Antibody Binds to Different beta-Amyloid Species, Inhibits Fibril Formation, and Disaggregates Preformed Fibrils but Not the Most Toxic Oligomers.
G. Mamikonyan, M. Necula, M. Mkrtichyan, A. Ghochikyan, I. Petrushina, N. Movsesyan, E. Mina, A. Kiyatkin, C. G. Glabe, D. H. Cribbs, et al. (2007)
J. Biol. Chem. 282, 22376-22386
   Abstract »    Full Text »    PDF »
Reduced Vesicular Storage of Dopamine Causes Progressive Nigrostriatal Neurodegeneration.
W. M. Caudle, J. R. Richardson, M. Z. Wang, T. N. Taylor, T. S. Guillot, A. L. McCormack, R. E. Colebrooke, D. A. Di Monte, P. C. Emson, and G. W. Miller (2007)
J. Neurosci. 27, 8138-8148
   Abstract »    Full Text »    PDF »
A cell biological perspective on mitochondrial dysfunction in Parkinson disease and other neurodegenerative diseases.
W. Mandemakers, V. A. Morais, and B. De Strooper (2007)
J. Cell Sci. 120, 1707-1716
   Abstract »    Full Text »    PDF »
Small Molecule Inhibitors of Aggregation Indicate That Amyloid beta Oligomerization and Fibrillization Pathways Are Independent and Distinct.
M. Necula, R. Kayed, S. Milton, and C. G. Glabe (2007)
J. Biol. Chem. 282, 10311-10324
   Abstract »    Full Text »    PDF »
Protective Effect of Sulforaphane against Dopaminergic Cell Death.
J. M. Han, Y. J. Lee, S. Y. Lee, E. M. Kim, Y. Moon, H. W. Kim, and O. Hwang (2007)
J. Pharmacol. Exp. Ther. 321, 249-256
   Abstract »    Full Text »    PDF »
A Drosophila Model of Mutant Human Parkin-Induced Toxicity Demonstrates Selective Loss of Dopaminergic Neurons and Dependence on Cellular Dopamine.
T.-K. Sang, H.-Y. Chang, G. M. Lawless, A. Ratnaparkhi, L. Mee, L. C. Ackerson, N. T. Maidment, D. E. Krantz, and G. R. Jackson (2007)
J. Neurosci. 27, 981-992
   Abstract »    Full Text »    PDF »
Dyrk1A Phosphorylates {alpha}-Synuclein and Enhances Intracellular Inclusion Formation.
E. J. Kim, J. Y. Sung, H. J. Lee, H. Rhim, M. Hasegawa, T. Iwatsubo, D. S. Min, J. Kim, S. R. Paik, and K. C. Chung (2006)
J. Biol. Chem. 281, 33250-33257
   Abstract »    Full Text »    PDF »
Cytosolic Catechols Inhibit {alpha}-Synuclein Aggregation and Facilitate the Formation of Intracellular Soluble Oligomeric Intermediates.
J. R. Mazzulli, A. J. Mishizen, B. I. Giasson, D. R. Lynch, S. A. Thomas, A. Nakashima, T. Nagatsu, A. Ota, and H. Ischiropoulos (2006)
J. Neurosci. 26, 10068-10078
   Abstract »    Full Text »    PDF »
A Potential Role for Cyclized Quinones Derived from Dopamine, DOPA, and 3,4-Dihydroxyphenylacetic Acid in Proteasomal Inhibition.
K. S. Zafar, D. Siegel, and D. Ross (2006)
Mol. Pharmacol. 70, 1079-1086
   Abstract »    Full Text »    PDF »
Etiology of Parkinson's disease.
A. H.V. Schapira (2006)
Neurology 66, S10-S23
   Abstract »    Full Text »
Detection of oligomeric forms of {alpha}-synuclein protein in human plasma as a potential biomarker for Parkinson's disease.
O. M. A. El-Agnaf, S. A. Salem, K. E. Paleologou, M. D. Curran, M. J. Gibson, J. A. Court, M. G. Schlossmacher, and D. Allsop (2006)
FASEB J 20, 419-425
   Abstract »    Full Text »    PDF »
Lewy bodies.
C. W. Shults (2006)
PNAS 103, 1661-1668
   Abstract »    Full Text »    PDF »
Gain-of-function haplotypes in the vesicular monoamine transporter promoter are protective for Parkinson disease in women.
C. E. Glatt, A. D. Wahner, D. J. White, A. Ruiz-Linares, and B. Ritz (2006)
Hum. Mol. Genet. 15, 299-305
   Abstract »    Full Text »    PDF »
Familial Parkinson Mutant {alpha}-Synuclein Causes Dopamine Neuron Dysfunction in Transgenic Caenorhabditis elegans.
T. Kuwahara, A. Koyama, K. Gengyo-Ando, M. Masuda, H. Kowa, M. Tsunoda, S. Mitani, and T. Iwatsubo (2006)
J. Biol. Chem. 281, 334-340
   Abstract »    Full Text »    PDF »
Similar Patterns of Mitochondrial Vulnerability and Rescue Induced by Genetic Modification of {alpha}-Synuclein, Parkin, and DJ-1 in Caenorhabditis elegans.
R. Ved, S. Saha, B. Westlund, C. Perier, L. Burnam, A. Sluder, M. Hoener, C. M. P. Rodrigues, A. Alfonso, C. Steer, et al. (2005)
J. Biol. Chem. 280, 42655-42668
   Abstract »    Full Text »    PDF »
Altered Gene Expression Profiles Reveal Similarities and Differences Between Parkinson Disease and Model Systems.
R. M. Miller and H. J. Federoff (2005)
Neuroscientist 11, 539-549
   Abstract »    PDF »
Molecular pathogenesis of Parkinson's disease.
S. Gandhi and N. W. Wood (2005)
Hum. Mol. Genet. 14, 2749-2755
   Abstract »    Full Text »    PDF »
Reversible Inhibition of {alpha}-Synuclein Fibrillization by Dopaminochrome-mediated Conformational Alterations.
E. H. Norris, B. I. Giasson, R. Hodara, S. Xu, J. Q. Trojanowski, H. Ischiropoulos, and V. M.-Y. Lee (2005)
J. Biol. Chem. 280, 21212-21219
   Abstract »    Full Text »    PDF »
Torsin-Mediated Protection from Cellular Stress in the Dopaminergic Neurons of Caenorhabditis elegans.
S. Cao, C. C. Gelwix, K. A. Caldwell, and G. A. Caldwell (2005)
J. Neurosci. 25, 3801-3812
   Abstract »    Full Text »    PDF »
Aggregated {alpha}-synuclein activates microglia: a process leading to disease progression in Parkinson's disease.
W. Zhang, T. Wang, Z. Pei, D. S. Miller, X. Wu, M. L. Block, B. Wilson, W. Zhang, Y. Zhou, J.-S. Hong, et al. (2005)
FASEB J 19, 533-542
   Abstract »    Full Text »    PDF »
Metal-catalyzed Oxidation of {alpha}-Synuclein: HELPING TO DEFINE THE RELATIONSHIP BETWEEN OLIGOMERS, PROTOFIBRILS, AND FILAMENTS.
N. B. Cole, D. D. Murphy, J. Lebowitz, L. Di Noto, R. L. Levine, and R. L. Nussbaum (2005)
J. Biol. Chem. 280, 9678-9690
   Abstract »    Full Text »    PDF »
Inhibition of Heparin-induced Tau Filament Formation by Phenothiazines, Polyphenols, and Porphyrins.
S. Taniguchi, N. Suzuki, M. Masuda, S.-i. Hisanaga, T. Iwatsubo, M. Goedert, and M. Hasegawa (2005)
J. Biol. Chem. 280, 7614-7623
   Abstract »    Full Text »    PDF »
p25{alpha} Stimulates {alpha}-Synuclein Aggregation and Is Co-localized with Aggregated {alpha}-Synuclein in {alpha}-Synucleinopathies.
E. Lindersson, D. Lundvig, C. Petersen, P. Madsen, J. R. Nyengaard, P. Hojrup, T. Moos, D. Otzen, W.-P. Gai, P. C. Blumbergs, et al. (2005)
J. Biol. Chem. 280, 5703-5715
   Abstract »    Full Text »    PDF »
Lentiviral vector delivery of parkin prevents dopaminergic degeneration in an {alpha}-synuclein rat model of Parkinson's disease.
C. Lo Bianco, B. L. Schneider, M. Bauer, A. Sajadi, A. Brice, T. Iwatsubo, and P. Aebischer (2004)
PNAS 101, 17510-17515
   Abstract »    Full Text »    PDF »
Functional Consequences of {alpha}-Synuclein Tyrosine Nitration: DIMINISHED BINDING TO LIPID VESICLES AND INCREASED FIBRIL FORMATION.
R. Hodara, E. H. Norris, B. I. Giasson, A. J. Mishizen-Eberz, D. R. Lynch, V. M.-Y. Lee, and H. Ischiropoulos (2004)
J. Biol. Chem. 279, 47746-47753
   Abstract »    Full Text »    PDF »
Biochemical, Ultrastructural, and Reversibility Studies on Huntingtin Filaments Isolated from Mouse and Human Brain.
M. Diaz-Hernandez, F. Moreno-Herrero, P. Gomez-Ramos, M. A. Moran, I. Ferrer, A. M. Baro, J. Avila, F. Hernandez, and J. J. Lucas (2004)
J. Neurosci. 24, 9361-9371
   Abstract »    Full Text »    PDF »
{beta}-Synuclein gene alterations in dementia with Lewy bodies.
H. Ohtake, P. Limprasert, Y. Fan, O. Onodera, A. Kakita, H. Takahashi, L. T. Bonner, D. W. Tsuang, I. V.J. Murray, V. M.-Y. Lee, et al. (2004)
Neurology 63, 805-811
   Abstract »    Full Text »    PDF »
{alpha}-Synuclein Has a High Affinity for Packing Defects in a Bilayer Membrane: A THERMODYNAMICS STUDY.
B. Nuscher, F. Kamp, T. Mehnert, S. Odoy, C. Haass, P. J. Kahle, and K. Beyer (2004)
J. Biol. Chem. 279, 21966-21975
   Abstract »    Full Text »    PDF »
Metabolite-initiated protein misfolding may trigger Alzheimer's disease.
Q. Zhang, E. T. Powers, J. Nieva, M. E. Huff, M. A. Dendle, J. Bieschke, C. G. Glabe, A. Eschenmoser, P. Wentworth Jr., R. A. Lerner, et al. (2004)
PNAS 101, 4752-4757
   Abstract »    Full Text »    PDF »
Does {alpha}-synuclein modulate dopaminergic synaptic content and tone at the synapse?.
A. SIDHU, C. WERSINGER, and P. VERNIER (2004)
FASEB J 18, 637-647
   Abstract »    Full Text »    PDF »
Proteasomal Inhibition by {alpha}-Synuclein Filaments and Oligomers.
E. Lindersson, R. Beedholm, P. Hojrup, T. Moos, W. Gai, K. B. Hendil, and P. H. Jensen (2004)
J. Biol. Chem. 279, 12924-12934
   Abstract »    Full Text »    PDF »
Parkin and {alpha}-Synuclein: Opponent Actions in The Pathogenesis of Parkinson'S Disease.
M. J. Baptista, M. R. Cookson, and D. W. Miller (2004)
Neuroscientist 10, 63-72
   Abstract »    PDF »
Instability of the Apo Form of Aromatic L-Amino Acid Decarboxylase In Vivo and In Vitro: Implications for the Involvement of the Flexible Loop That Covers the Active Site.
N. Matsuda, H. Hayashi, S. Miyatake, T. Kuroiwa, and H. Kagamiyama (2004)
J. Biochem. 135, 33-42
   Abstract »    Full Text »    PDF »
Molecular Pathways of Neurodegeneration in Parkinson's Disease.
T. M. Dawson and V. L. Dawson (2003)
Science 302, 819-822
   Abstract »    Full Text »    PDF »
Dopamine-dependent neurodegeneration in rats induced by viral vector-mediated overexpression of the parkin target protein, CDCrel-1.
Z. Dong, B. Ferger, J.-C. Paterna, D. Vogel, S. Furler, M. Osinde, J. Feldon, and H. Bueler (2003)
PNAS 100, 12438-12443
   Abstract »    Full Text »    PDF »
Fine Structure and Biochemical Mechanisms Underlying Nigrostriatal Inclusions and Cell Death after Proteasome Inhibition.
F. Fornai, P. Lenzi, M. Gesi, M. Ferrucci, G. Lazzeri, C. L. Busceti, R. Ruffoli, P. Soldani, S. Ruggieri, M. G. Alessandri, et al. (2003)
J. Neurosci. 23, 8955-8966
   Abstract »    Full Text »    PDF »
Gene expression changes presage neurodegeneration in a Drosophila model of Parkinson's disease.
C. R. Scherzer, R. V. Jensen, S. R. Gullans, and M. B. Feany (2003)
Hum. Mol. Genet. 12, 2457-2466
   Abstract »    Full Text »    PDF »
Imaging the dopamine system to assess disease-modifying drugs: Studies comparing dopamine agonists and levodopa.
K. Marek, D. Jennings, and J. Seibyl (2003)
Neurology 61, S43-48
   Full Text »
Certain Metals Trigger Fibrillation of Methionine-oxidized {alpha}-Synuclein.
G. Yamin, C. B. Glaser, V. N. Uversky, and A. L. Fink (2003)
J. Biol. Chem. 278, 27630-27635
   Abstract »    Full Text »    PDF »
Effects of Oxidative and Nitrative Challenges on {alpha}-Synuclein Fibrillogenesis Involve Distinct Mechanisms of Protein Modifications.
E. H. Norris, B. I. Giasson, H. Ischiropoulos, and V. M.-Y. Lee (2003)
J. Biol. Chem. 278, 27230-27240
   Abstract »    Full Text »    PDF »
Intracellular Patch Electrochemistry: Regulation of Cytosolic Catecholamines in Chromaffin Cells.
E. V. Mosharov, L.-W. Gong, B. Khanna, D. Sulzer, and M. Lindau (2003)
J. Neurosci. 23, 5835-5845
   Abstract »    Full Text »    PDF »
Identification and functional characterization of a novel R621C mutation in the synphilin-1 gene in Parkinson's disease.
F. P. Marx, C. Holzmann, K. M. Strauss, L. Li, O. Eberhardt, E. Gerhardt, M. R. Cookson, D. Hernandez, M. J. Farrer, J. Kachergus, et al. (2003)
Hum. Mol. Genet. 12, 1223-1231
   Abstract »    Full Text »    PDF »
Cyclooxygenase-2 is instrumental in Parkinson's disease neurodegeneration.
P. Teismann, K. Tieu, D.-K. Choi, D.-C. Wu, A. Naini, S. Hunot, M. Vila, V. Jackson-Lewis, and S. Przedborski (2003)
PNAS 100, 5473-5478
   Abstract »    Full Text »    PDF »
Cocaine Abusers Have an Overexpression of alpha -Synuclein in Dopamine Neurons.
D. C. Mash, Q. Ouyang, J. Pablo, M. Basile, S. Izenwasser, A. Lieberman, and R. J. Perrin (2003)
J. Neurosci. 23, 2564-2571
   Abstract »    Full Text »    PDF »
Nigrostriatal alpha -synucleinopathy induced by viral vector-mediated overexpression of human alpha -synuclein: A new primate model of Parkinson's disease.
D. Kirik, L. E. Annett, C. Burger, N. Muzyczka, R. J. Mandel, and A. Bjorklund (2003)
PNAS 100, 2884-2889
   Abstract »    Full Text »    PDF »
Cellular Polyamines Promote the Aggregation of alpha -Synuclein.
T. Antony, W. Hoyer, D. Cherny, G. Heim, T. M. Jovin, and V. Subramaniam (2003)
J. Biol. Chem. 278, 3235-3240
   Abstract »    Full Text »    PDF »
Trophic Restoration of the Nigrostriatal Dopaminergic Pathway in Long-Term Carotid Body-Grafted Parkinsonian Rats.
J. J. Toledo-Aral, S. Mendez-Ferrer, R. Pardal, M. Echevarria, and J. Lopez-Barneo (2003)
J. Neurosci. 23, 141-148
   Abstract »    Full Text »    PDF »
Golgi Fragmentation Occurs in the Cells with Prefibrillar alpha -Synuclein Aggregates and Precedes the Formation of Fibrillar Inclusion.
N. Gosavi, H.-J. Lee, J. S. Lee, S. Patel, and S.-J. Lee (2002)
J. Biol. Chem. 277, 48984-48992
   Abstract »    Full Text »    PDF »
New Class of Inhibitors of Amyloid-beta Fibril Formation. IMPLICATIONS FOR THE MECHANISM OF PATHOGENESIS IN ALZHEIMER'S DISEASE.
H. A. Lashuel, D. M. Hartley, D. Balakhaneh, A. Aggarwal, S. Teichberg, and D. J. E. Callaway (2002)
J. Biol. Chem. 277, 42881-42890
   Abstract »    Full Text »    PDF »
Etiology of Parkinson's disease: Genetics and environment revisited.
K. Steece-Collier, E. Maries, and J. H. Kordower (2002)
PNAS 99, 13972-13974
   Full Text »    PDF »
From the Cover: Resistance of alpha -synuclein null mice to the parkinsonian neurotoxin MPTP.
W. Dauer, N. Kholodilov, M. Vila, A.-C. Trillat, R. Goodchild, K. E. Larsen, R. Staal, K. Tieu, Y. Schmitz, C. A. Yuan, et al. (2002)
PNAS 99, 14524-14529
   Abstract »    Full Text »    PDF »
Huntingtin Spheroids and Protofibrils as Precursors in Polyglutamine Fibrilization.
M. A. Poirier, H. Li, J. Macosko, S. Cai, M. Amzel, and C. A. Ross (2002)
J. Biol. Chem. 277, 41032-41037
   Abstract »    Full Text »    PDF »
Effect of Mutant alpha -Synuclein on Dopamine Homeostasis in a New Human Mesencephalic Cell Line.
J. Lotharius, S. Barg, P. Wiekop, C. Lundberg, H. K. Raymon, and P. Brundin (2002)
J. Biol. Chem. 277, 38884-38894
   Abstract »    Full Text »    PDF »
The genetic basis of Parkinson's disease.
T Foltynie, S Sawcer, C Brayne, and R A Barker (2002)
J. Neurol. Neurosurg. Psychiatry 73, 363-370
   Abstract »    Full Text »    PDF »
Impaired dopamine storage resulting from {alpha}-synuclein mutations may contribute to the pathogenesis of Parkinson's disease.
J. Lotharius and P. Brundin (2002)
Hum. Mol. Genet. 11, 2395-2407
   Abstract »    Full Text »    PDF »
Amyloid Precursor Protein, Presenilins, and alpha -Synuclein: Molecular Pathogenesis and Pharmacological Applications in Alzheimer's Disease.
Y.-H. Suh and F. Checler (2002)
Pharmacol. Rev. 54, 469-525
   Abstract »    Full Text »    PDF »
Neurodegeneration in the age of molecular biology.
L. I Golbe (2002)
BMJ 324, 1467-1468
   Full Text »    PDF »
A Role for alpha -Synuclein in the Regulation of Dopamine Biosynthesis.
R. G. Perez, J. C. Waymire, E. Lin, J. J. Liu, F. Guo, and M. J. Zigmond (2002)
J. Neurosci. 22, 3090-3099
   Abstract »    Full Text »    PDF »
Neurotoxin-induced degeneration of dopamine neurons in Caenorhabditis elegans.
R. Nass, D. H. Hall, D. M. Miller III, and R. D. Blakely (2002)
PNAS
   Abstract »    Full Text »    PDF »
Neuropathological Verisimilitude in Animal Models of Alzheimer's Disease : Key to Elucidating Neurodegenerative Pathways and Identifying New Targets for Drug Discovery.
J. Q. Trojanowski (2002)
Am. J. Pathol. 160, 409-411
   Full Text »    PDF »
Neurotoxin-induced degeneration of dopamine neurons in Caenorhabditis elegans.
R. Nass, D. H. Hall, D. M. Miller III, and R. D. Blakely (2002)
PNAS 99, 3264-3269
   Abstract »    Full Text »    PDF »


To Advertise     Find Products

Science. ISSN 0036-8075 (print), 1095-9203 (online)