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J Biol Chem, Vol. 274, Issue 12, 7619-7622, March 19, 1999
-Synucleins Assemble into Elongated
Filaments with Distinct Morphologies in Vitro
From the Department of Pathology and Laboratory Medicine,
University of Pennsylvania School of Medicine,
Philadelphia, Pennsylvania 19104
-Synuclein is a soluble presynaptic protein
which is pathologically redistributed within intracellular lesions
characteristic of several neurodegenerative diseases. Here we
demonstrate that wild type and two mutant forms of -synuclein linked
to familial Parkinson's disease (Ala30 
Pro and
Ala53 Thr) self-aggregate and assemble into
10-19-nm-wide filaments with distinct morphologies under defined
in vitro conditions. Immunogold labeling demonstrates that
the central region of all these filaments are more robustly labeled
than the N-terminal or C-terminal regions, suggesting that the latter
regions are buried within the filaments. Since in vitro
generated -synuclein filaments resemble the major ultrastructural
elements of authentic Lewy bodies that are hallmark lesions of
Parkinson's disease, we propose that self-aggregating -synuclein is
the major subunit protein of these filamentous lesions.
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J. E. Duda, B. I. Giasson, Q. Chen, T. L. Gur, H. I. Hurtig, M. B. Stern, S. M. Gollomp, H. Ischiropoulos, V. M.-Y. Lee, and J. Q. Trojanowski Widespread Nitration of Pathological Inclusions in Neurodegenerative Synucleinopathies Am. J. Pathol., November 1, 2000; 157(5): 1439 - 1445. [Abstract] [Full Text] [PDF]
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P. J. Kahle, M. Neumann, L. Ozmen, V. Muller, H. Jacobsen, A. Schindzielorz, M. Okochi, U. Leimer, H. van der Putten, A. Probst, et al. Subcellular Localization of Wild-Type and Parkinson's Disease-Associated Mutant alpha -Synuclein in Human and Transgenic Mouse Brain J. Neurosci., September 1, 2000; 20(17): 6365 - 6373. [Abstract] [Full Text] [PDF]
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H. van der Putten, K.-H. Wiederhold, A. Probst, S. Barbieri, C. Mistl, S. Danner, S. Kauffmann, K. Hofele, W. P. J. M. Spooren, M. A. Ruegg, et al. Neuropathology in Mice Expressing Human alpha -Synuclein J. Neurosci., August 15, 2000; 20(16): 6021 - 6029. [Abstract] [Full Text] [PDF]
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D. D. Murphy, S. M. Rueter, J. Q. Trojanowski, and V. M.-Y. Lee Synucleins Are Developmentally Expressed, and alpha -Synuclein Regulates the Size of the Presynaptic Vesicular Pool in Primary Hippocampal Neurons J. Neurosci., May 1, 2000; 20(9): 3214 - 3220. [Abstract] [Full Text] [PDF]
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L. C. Serpell, J. Berriman, R. Jakes, M. Goedert, and R. A. Crowther Fiber diffraction of synthetic alpha -synuclein filaments shows amyloid-like cross-beta conformation PNAS, April 25, 2000; 97(9): 4897 - 4902. [Abstract] [Full Text] [PDF]
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K. A. Conway, S.-J. Lee, J.-C. Rochet, T. T. Ding, R. E. Williamson, and P. T. Lansbury Jr. 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 PNAS, January 18, 2000; 97(2): 571 - 576. [Abstract] [Full Text] [PDF]
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M. Okochi, J. Walter, A. Koyama, S. Nakajo, M. Baba, T. Iwatsubo, L. Meijer, P. J. Kahle, and C. Haass Constitutive Phosphorylation of the Parkinson's Disease Associated alpha -Synuclein J. Biol. Chem., January 7, 2000; 275(1): 390 - 397. [Abstract] [Full Text] [PDF]
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M. C. Bennett, J. F. Bishop, Y. Leng, P. B. Chock, T. N. Chase, and M. M. Mouradian Degradation of alpha -Synuclein by Proteasome J. Biol. Chem., November 26, 1999; 274(48): 33855 - 33858. [Abstract] [Full Text] [PDF]
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M. Farrer, K. Gwinn-Hardy, M. Hutton, and J. Hardy The genetics of disorders withsynuclein pathology and parkinsonism Hum. Mol. Genet., September 1, 1999; 8(10): 1901 - 1905. [Abstract] [Full Text] [PDF]
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S. J. Wood, J. Wypych, S. Steavenson, J.-C. Louis, M. Citron, and A. L. Biere alpha -Synuclein Fibrillogenesis Is Nucleation-dependent. IMPLICATIONS FOR THE PATHOGENESIS OF PARKINSON'S DISEASE J. Biol. Chem., July 9, 1999; 274(28): 19509 - 19512. [Abstract] [Full Text] [PDF]
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P. H. Jensen, K. Islam, J. Kenney, M. S. Nielsen, J. Power, and W. P. Gai Microtubule-associated Protein 1B Is a Component of Cortical Lewy Bodies and Binds alpha -Synuclein Filaments J. Biol. Chem., July 7, 2000; 275(28): 21500 - 21507. [Abstract] [Full Text] [PDF]
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J. M. Souza, B. I. Giasson, Q. Chen, V. M.-Y. Lee, and H. Ischiropoulos Dityrosine Cross-linking Promotes Formation of Stable alpha -Synuclein Polymers. IMPLICATION OF NITRATIVE AND OXIDATIVE STRESS IN THE PATHOGENESIS OF NEURODEGENERATIVE SYNUCLEINOPATHIES J. Biol. Chem., June 9, 2000; 275(24): 18344 - 18349. [Abstract] [Full Text] [PDF]
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E. Jo, J. McLaurin, C. M. Yip, P. St. George-Hyslop, and P. E. Fraser alpha -Synuclein Membrane Interactions and Lipid Specificity J. Biol. Chem., October 27, 2000; 275(44): 34328 - 34334. [Abstract] [Full Text] [PDF]
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A. L. Biere, S. J. Wood, J. Wypych, S. Steavenson, Y. Jiang, D. Anafi, F. W. Jacobsen, M. A. Jarosinski, G.-M. Wu, J.-C. Louis, et al. Parkinson's Disease-associated alpha -Synuclein Is More Fibrillogenic than beta - and gamma -Synuclein and Cannot Cross-seed Its Homologs J. Biol. Chem., October 27, 2000; 275(44): 34574 - 34579. [Abstract] [Full Text] [PDF]
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B. I. Giasson, I. V. J. Murray, J. Q. Trojanowski, and V. M.-Y. Lee A Hydrophobic Stretch of 12 Amino Acid Residues in the Middle of alpha -Synuclein Is Essential for Filament Assembly J. Biol. Chem., January 19, 2001; 276(4): 2380 - 2386. [Abstract] [Full Text] [PDF]
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A. Iwata, M. Maruyama, I. Kanazawa, and N. Nukina alpha -Synuclein Affects the MAPK Pathway and Accelerates Cell Death J. Biol. Chem., November 21, 2001; 276(48): 45320 - 45329. [Abstract] [Full Text] [PDF]
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