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Originally published in Science Express on 20 December 2001
Science 1 February 2002:
Vol. 295. no. 5556, pp. 865 - 868
DOI: 10.1126/science.1067389
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Reports

Chaperone Suppression of alpha -Synuclein Toxicity in a Drosophila Model for Parkinson's Disease

Pavan K. Auluck,1 H. Y. Edwin Chan,2* John Q. Trojanowski,3 Virginia M.-Y. Lee,3 Nancy M. Bonini124dagger

Parkinson's disease is a movement disorder characterized by degeneration of dopaminergic neurons in the substantia nigra pars compacta. Dopaminergic neuronal loss also occurs in Drosophila melanogaster upon directed expression of alpha -synuclein, a protein implicated in the pathogenesis of Parkinson's disease and a major component of proteinaceous Lewy bodies. We report that directed expression of the molecular chaperone Hsp70 prevented dopaminergic neuronal loss associated with alpha -synuclein in Drosophila and that interference with endogenous chaperone activity accelerated alpha -synuclein toxicity. Furthermore, Lewy bodies in human postmortem tissue immunostained for molecular chaperones, also suggesting that chaperones may play a role in Parkinson's disease progression.

1 Department of Neuroscience,
2 Department of Biology,
3 Center for Neurodegenerative Disease Research and Department of Pathology and Laboratory Medicine, and
4 Howard Hughes Medical Institute, University of Pennsylvania and University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
*   Present address: Department of Biochemistry, The Chinese University of Hong Kong, Shatin, Hong Kong.

dagger    To whom correspondence should be addressed. E-mail: nbonini{at}sas.upenn.edu

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Integrative Physiology and Functional Genomics of Epithelial Function in a Genetic Model Organism.
J. A. T. DOW and S. A. DAVIES (2003)
Physiol Rev 83, 687-729
   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 »
Parkin Facilitates the Elimination of Expanded Polyglutamine Proteins and Leads to Preservation of Proteasome Function.
Y. C. Tsai, P. S. Fishman, N. V. Thakor, and G. A. Oyler (2003)
J. Biol. Chem. 278, 22044-22055
   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 »
Genetic modifiers in human development and malformation syndromes, including chaperone proteins.
A. Slavotinek and L. G. Biesecker (2003)
Hum. Mol. Genet. 12, R45-50
   Abstract »    Full Text »    PDF »
Genomic convergence: identifying candidate genes for Parkinson's disease by combining serial analysis of gene expression and genetic linkage.
M. A. Hauser, Y.-J. Li, S. Takeuchi, R. Walters, M. Noureddine, M. Maready, T. Darden, C. Hulette, E. Martin, E. Hauser, et al. (2003)
Hum. Mol. Genet. 12, 671-677
   Abstract »    Full Text »    PDF »
blue cheese Mutations Define a Novel, Conserved Gene Involved in Progressive Neural Degeneration.
K. D. Finley, P. T. Edeen, R. C. Cumming, M. D. Mardahl-Dumesnil, B. J. Taylor, M. H. Rodriguez, C. E. Hwang, M. Benedetti, and M. McKeown (2003)
J. Neurosci. 23, 1254-1264
   Abstract »    Full Text »    PDF »
Suppression of polyglutamine-induced protein aggregation in Caenorhabditis elegans by torsin proteins.
G. A. Caldwell, S. Cao, E. G. Sexton, C. C. Gelwix, J. P. Bevel, and K. A. Caldwell (2003)
Hum. Mol. Genet. 12, 307-319
   Abstract »    Full Text »    PDF »
Chaperones increase association of tau protein with microtubules.
F. Dou, W. J. Netzer, K. Tanemura, F. Li, F. U. Hartl, A. Takashima, G. K. Gouras, P. Greengard, and H. Xu (2003)
PNAS 100, 721-726
   Abstract »    Full Text »    PDF »
Characterization of Cytoplasmic alpha -Synuclein Aggregates. FIBRIL FORMATION IS TIGHTLY LINKED TO THE INCLUSION-FORMING PROCESS IN CELLS.
H.-J. Lee and S.-J. Lee (2002)
J. Biol. Chem. 277, 48976-48983
   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 »
Parkin Accumulation in Aggresomes Due to Proteasome Impairment.
E. Junn, S. S. Lee, U. T. Suhr, and M. M. Mouradian (2002)
J. Biol. Chem. 277, 47870-47877
   Abstract »    Full Text »    PDF »
Suppression of polyglutamine toxicity by a Drosophila homolog of myeloid leukemia factor 1.
P. Kazemi-Esfarjani and S. Benzer (2002)
Hum. Mol. Genet. 11, 2657-2672
   Abstract »    Full Text »    PDF »
The threshold for polyglutamine-expansion protein aggregation and cellular toxicity is dynamic and influenced by aging in Caenorhabditiselegans.
J. F. Morley, H. R. Brignull, J. J. Weyers, and R. I. Morimoto (2002)
PNAS 99, 10417-10422
   Abstract »    Full Text »    PDF »
Interaction of intracellular beta amyloid peptide with chaperone proteins.
V. Fonte, V. Kapulkin, A. Taft, A. Fluet, D. Friedman, and C. D. Link (2002)
PNAS 99, 9439-9444
   Abstract »    Full Text »    PDF »
Toxic Proteins in Neurodegenerative Disease.
J. P. Taylor, J. Hardy, and K. H. Fischbeck (2002)
Science 296, 1991-1995
   Abstract »    Full Text »    PDF »


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