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Science 18 February 2000:
Vol. 287. no. 5456, pp. 1265 - 1269
DOI: 10.1126/science.287.5456.1265
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Reports

Dopaminergic Loss and Inclusion Body Formation in alpha -Synuclein Mice: Implications for Neurodegenerative Disorders

Eliezer Masliah, 12* Edward Rockenstein, 1 Isaac Veinbergs, 2 Margaret Mallory, 1 Makoto Hashimoto, 1 Ayako Takeda, 13 Yutaka Sagara, 2 Abbyann Sisk, 2 Lennart Mucke 4

To elucidate the role of the synaptic protein alpha -synuclein in neurodegenerative disorders, transgenic mice expressing wild-type human alpha -synuclein were generated. Neuronal expression of human alpha -synuclein resulted in progressive accumulation of alpha -synuclein--and ubiquitin-immunoreactive inclusions in neurons in the neocortex, hippocampus, and substantia nigra. Ultrastructural analysis revealed both electron-dense intranuclear deposits and cytoplasmic inclusions. These alterations were associated with loss of dopaminergic terminals in the basal ganglia and with motor impairments. These results suggest that accumulation of wild-type alpha -synuclein may play a causal role in Parkinson's disease and related conditions.

1 Department of Neurosciences,
2 Department of Pathology, University of California San Diego, La Jolla, CA 92093-0624, USA.
3 Department of Psychiatry, Yokohama City University, School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236, Japan.
4 Gladstone Institute of Neurological Disease and Department of Neurology, University of California San Francisco, Post Office Box 419100, San Francisco, CA 94141-9100, USA.
*   To whom correspondence should be addressed. E-mail: emasliah{at}ucsd.edu

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   Abstract »    Full Text »    PDF »
Alpha-synuclein degradation by serine protease neurosin: implication for pathogenesis of synucleinopathies.
A. Iwata, M. Maruyama, T. Akagi, T. Hashikawa, I. Kanazawa, S. Tsuji, and N. Nukina (2003)
Hum. Mol. Genet. 12, 2625-2635
   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 »
Structural Organization of {alpha}-Synuclein Fibrils Studied by Site-directed Spin Labeling.
A. Der-Sarkissian, C. C. Jao, J. Chen, and R. Langen (2003)
J. Biol. Chem. 278, 37530-37535
   Abstract »    Full Text »    PDF »
LY503430, a Novel {alpha}-Amino-3-hydroxy-5-methylisoxazole-4-propionic Acid Receptor Potentiator with Functional, Neuroprotective and Neurotrophic Effects in Rodent Models of Parkinson's Disease.
T. K. Murray, K. Whalley, C. S. Robinson, M. A. Ward, C. A. Hicks, D. Lodge, J. L. Vandergriff, P. Baumbarger, E. Siuda, M. Gates, et al. (2003)
J. Pharmacol. Exp. Ther. 306, 752-762
   Abstract »    Full Text »    PDF »
Parkinson's disease: piecing together a genetic jigsaw.
M. C. J. Dekker, V. Bonifati, and C. M. van Duijn (2003)
Brain 126, 1722-1733
   Abstract »    Full Text »    PDF »
Dorfin Localizes to Lewy Bodies and Ubiquitylates Synphilin-1.
T. Ito, J.-i. Niwa, N. Hishikawa, S. Ishigaki, M. Doyu, and G. Sobue (2003)
J. Biol. Chem. 278, 29106-29114
   Abstract »    Full Text »    PDF »
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 »
Ubiquitination of {alpha}-Synuclein Is Not Required for Formation of Pathological Inclusions in {alpha}-Synucleinopathies.
D. M. Sampathu, B. I. Giasson, A. C. Pawlyk, J. Q. Trojanowski, and V. M.-Y. Lee (2003)
Am. J. Pathol. 163, 91-100
   Abstract »    Full Text »    PDF »
Subcellular localisation, secretion, and post-translational processing of normal cochlin, and of mutants causing the sensorineural deafness and vestibular disorder, DFNA9.
N G Robertson, S A Hamaker, V Patriub, J C Aster, and C C Morton (2003)
J. Med. Genet. 40, 479-486
   Abstract »    Full Text »    PDF »
{alpha}-Synuclein Is Degraded by Both Autophagy and the Proteasome.
J. L. Webb, B. Ravikumar, J. Atkins, J. N. Skepper, and D. C. Rubinsztein (2003)
J. Biol. Chem. 278, 25009-25013
   Abstract »    Full Text »    PDF »
Association of the Cytoskeletal GTP-binding Protein Sept4/H5 with Cytoplasmic Inclusions Found in Parkinson's Disease and Other Synucleinopathies.
M. Ihara, H. Tomimoto, H. Kitayama, Y. Morioka, I. Akiguchi, H. Shibasaki, M. Noda, and M. Kinoshita (2003)
J. Biol. Chem. 278, 24095-24102
   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 »
Parkinson's Disease-associated alpha -Synuclein Is a Calmodulin Substrate.
J. Martinez, I. Moeller, H. Erdjument-Bromage, P. Tempst, and B. Lauring (2003)
J. Biol. Chem. 278, 17379-17387
   Abstract »    Full Text »    PDF »
alpha -Synuclein Overexpression Protects against Paraquat-Induced Neurodegeneration.
A. B. Manning-Bog, A. L. McCormack, M. G. Purisai, L. M. Bolin, and D. A. Di Monte (2003)
J. Neurosci. 23, 3095-3099
   Abstract »    Full Text »    PDF »
alpha -Synuclein maps to a quantitative trait locus for alcohol preference and is differentially expressed in alcohol-preferring and -nonpreferring rats.
T. Liang, J. Spence, L. Liu, W. N. Strother, H. W. Chang, J. A. Ellison, L. Lumeng, T.-K. Li, T. Foroud, and L. G. Carr (2003)
PNAS 100, 4690-4695
   Abstract »    Full Text »    PDF »
Update on Parkinson Disease.
A. Siderowf and M. Stern (2003)
Ann Intern Med 138, 651-658
   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 »
Aggregated and Monomeric alpha -Synuclein Bind to the S6' Proteasomal Protein and Inhibit Proteasomal Function.
H. Snyder, K. Mensah, C. Theisler, J. Lee, A. Matouschek, and B. Wolozin (2003)
J. Biol. Chem. 278, 11753-11759
   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 »
Regulation of {alpha}-Synuclein Expression: Implications for Parkinson's Disease.
O. CHIBA-FALEK and R.L. NUSSBAUM (2003)
Cold Spring Harb Symp Quant Biol 68, 409-416
   Abstract »    PDF »
alpha -Synuclein Lowers p53-dependent Apoptotic Response of Neuronal Cells. ABOLISHMENT BY 6-HYDROXYDOPAMINE AND IMPLICATION FOR PARKINSON'S DISEASE.
C. Alves da Costa, E. Paitel, B. Vincent, and F. Checler (2002)
J. Biol. Chem. 277, 50980-50984
   Abstract »    Full Text »    PDF »


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