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Originally published in Science Express on 28 June 2001
Science 13 July 2001:
Vol. 293. no. 5528, pp. 263 - 269
DOI: 10.1126/science.1060627
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Research Articles

Ubiquitination of a New Form of alpha -Synuclein by Parkin from Human Brain: Implications for Parkinson's Disease

Hideki Shimura,12* Michael G. Schlossmacher,12*dagger Nobutaka Hattori,4 Matthew P. Frosch,123 Alexander Trockenbacher,5 Rainer Schneider,5 Yoshikuni Mizuno,4 Kenneth S. Kosik,12ddagger Dennis J. Selkoe12ddagger

Parkinson's disease (PD) is a common neurodegenerative disorder characterized by the progressive accumulation in selected neurons of protein inclusions containing alpha -synuclein and ubiquitin. Rare inherited forms of PD are caused by autosomal dominant mutations in alpha -synuclein or by autosomal recessive mutations in parkin, an E3 ubiquitin ligase. We hypothesized that these two gene products interact functionally, namely, that parkin ubiquitinates alpha -synuclein normally and that this process is altered in autosomal recessive PD. We have now identified a protein complex in normal human brain that includes parkin as the E3 ubiquitin ligase, UbcH7 as its associated E2 ubiquitin conjugating enzyme, and a new 22-kilodalton glycosylated form of alpha -synuclein (alpha Sp22) as its substrate. In contrast to normal parkin, mutant parkin associated with autosomal recessive PD failed to bind alpha Sp22. In an in vitro ubiquitination assay, alpha Sp22 was modified by normal but not mutant parkin into polyubiquitinated, high molecular weight species. Accordingly, alpha Sp22 accumulated in a non-ubiquitinated form in parkin-deficient PD brains. We conclude that alpha Sp22 is a substrate for parkin's ubiquitin ligase activity in normal human brain and that loss of parkin function causes pathological alpha Sp22 accumulation. These findings demonstrate a critical biochemical reaction between the two PD-linked gene products and suggest that this reaction underlies the accumulation of ubiquitinated alpha -synuclein in conventional PD.

1 Center for Neurologic Diseases,
2 Department of Neurology,
3 Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
4 Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan.
5 Institute of Biochemistry, University of Innsbruck, Innsbruck, Austria.
*   These authors contributed equally to this work.

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

ddagger    These authors contributed equally to this work.

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   Abstract »    Full Text »    PDF »
Ubiquitination of {alpha}-Synuclein in Lewy Bodies Is a Pathological Event Not Associated with Impairment of Proteasome Function.
G. K. Tofaris, A. Razzaq, B. Ghetti, K. S. Lilley, and M. G. Spillantini (2003)
J. Biol. Chem. 278, 44405-44411
   Abstract »    Full Text »    PDF »
Disease-specific accumulation of mutant ubiquitin as a marker for proteasomal dysfunction in the brain.
D. F. FISCHER, R. A. I. DE VOS, R. VAN DIJK, F. M. S. DE VRIJ, E. A. PROPER, M. A. F. SONNEMANS, M. C. VERHAGE, J. A. SLUIJS, B. HOBO, M. ZOUAMBIA, et al. (2003)
FASEB J 17, 2014-2024
   Abstract »    Full Text »    PDF »
The DJ-1L166P mutant protein associated with early onset Parkinson's disease is unstable and forms higher-order protein complexes.
M. G. Macedo, B. Anar, I. F. Bronner, M. Cannella, F. Squitieri, V. Bonifati, A. Hoogeveen, P. Heutink, and P. Rizzu (2003)
Hum. Mol. Genet. 12, 2807-2816
   Abstract »    Full Text »    PDF »
Inhibition of Proteasomal Activity Causes Inclusion Formation in Neuronal and Non-Neuronal Cells Overexpressing Parkin.
H. C. Ardley, G. B. Scott, S. A. Rose, N. G. S. Tan, A. F. Markham, and P. A. Robinson (2003)
Mol. Biol. Cell 14, 4541-4556
   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 »
Parkin-deficient Mice Exhibit Nigrostriatal Deficits but Not Loss of Dopaminergic Neurons.
M. S. Goldberg, S. M. Fleming, J. J. Palacino, C. Cepeda, H. A. Lam, A. Bhatnagar, E. G. Meloni, N. Wu, L. C. Ackerson, G. J. Klapstein, et al. (2003)
J. Biol. Chem. 278, 43628-43635
   Abstract »    Full Text »    PDF »
Parkin Cleaves Intracellular {alpha}-Synuclein Inclusions via the Activation of Calpain.
S. J. Kim, J. Y. Sung, J. W. Um, N. Hattori, Y. Mizuno, K. Tanaka, S. R. Paik, J. Kim, and K. C. Chung (2003)
J. Biol. Chem. 278, 41890-41899
   Abstract »    Full Text »    PDF »
The autosomal recessive juvenile Parkinson disease gene product, parkin, interacts with and ubiquitinates synaptotagmin XI.
D. P. Huynh, D. R. Scoles, D. Nguyen, and S. M. Pulst (2003)
Hum. Mol. Genet. 12, 2587-2597
   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 »
Parkin is recruited to the centrosome in response to inhibition of proteasomes.
J. Zhao, Y. Ren, Q. Jiang, and J. Feng (2003)
J. Cell Sci. 116, 4011-4019
   Abstract »    Full Text »    PDF »
Parkin gene inactivation alters behaviour and dopamine neurotransmission in the mouse.
J.-M. Itier, P. Ibanez, M. A. Mena, N. Abbas, C. Cohen-Salmon, G. A. Bohme, M. Laville, J. Pratt, O. Corti, L. Pradier, et al. (2003)
Hum. Mol. Genet. 12, 2277-2291
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Ubiquitin carboxy-terminal hydrolase L1 binds to and stabilizes monoubiquitin in neuron.
H. Osaka, Y.-L. Wang, K. Takada, S. Takizawa, R. Setsuie, H. Li, Y. Sato, K. Nishikawa, Y.-J. Sun, M. Sakurai, et al. (2003)
Hum. Mol. Genet. 12, 1945-1958
   Abstract »    Full Text »    PDF »
Dorfin Localizes to the Ubiquitylated Inclusions in Parkinson's Disease, Dementia with Lewy Bodies, Multiple System Atrophy, and Amyotrophic Lateral Sclerosis.
N. Hishikawa, J.-i. Niwa, M. Doyu, T. Ito, S. Ishigaki, Y. Hashizume, and G. Sobue (2003)
Am. J. Pathol. 163, 609-619
   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
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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 »
{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 »


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