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The Journal of Neuroscience, September 27, 2006, 26(39):10068-10078; doi:10.1523/JNEUROSCI.0896-06.2006

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Neurobiology of Disease
Cytosolic Catechols Inhibit {alpha}-Synuclein Aggregation and Facilitate the Formation of Intracellular Soluble Oligomeric Intermediates

Joseph R. Mazzulli,1 Amanda J. Mishizen,1,3 Benoit I. Giasson,2 David R. Lynch,1,3 Steven A. Thomas,2 Akira Nakashima,4 Toshiharu Nagatsu,5 Akira Ota,4 and Harry Ischiropoulos1,2,3

1The Joseph Stokes Jr. Research Institute and 2Departments of Pharmacology and 3Pediatrics, The Children's Hospital of Philadelphia and The University of Pennsylvania, Philadelphia, Pennsylvania 19104, and Departments of 4Physiology and 5Pharmacology, Fujita Health University School of Medicine, Toyoake, Aichi 470-1192, Japan

Correspondence should be addressed to Dr. Harry Ischiropoulos, Stokes Research Institute, Children's Hospital of Philadelphia, 416D Abramson Research Center, 3517 Civic Center Boulevard, Philadelphia, PA 19104-4318. Email: ischirop{at}mail.med.upenn.edu

Aberrant aggregation of {alpha}-synuclein ({alpha}-syn) to form fibrils and insoluble aggregates has been implicated in the pathogenic processes of many neurodegenerative diseases. Despite the dramatic effects of dopamine in inhibiting the formation of {alpha}-syn fibrils by stabilization of oligomeric intermediates in cell-free systems, no studies have examined the effects of intracellular dopamine on {alpha}-syn aggregation. To study this process and its association with neurodegeneration, intracellular catechol levels were increased to various levels by expressing different forms of tyrosine hydroxylase, in cells induced to form {alpha}-syn aggregates. The increase in the steady-state dopamine levels inhibited the formation of {alpha}-syn aggregates and induced the formation of innocuous oligomeric intermediates. Analysis of transgenic mice expressing the disease-associated A53T mutant {alpha}-syn revealed the presence of oligomeric {alpha}-syn in nondegenerating dopaminergic neurons that do contain insoluble {alpha}-syn. These data indicate that intraneuronal dopamine levels can be a major modulator of {alpha}-syn aggregation and inclusion formation, with important implications on the selective degeneration of these neurons in Parkinson's disease.

Key words: {alpha}-synuclein; catecholamines; neurodegeneration; Parkinson's disease; tyrosine hydroxylase; protein aggregation

Received Feb. 28, 2006; revised Aug. 11, 2006; accepted Aug. 13, 2006.

Correspondence should be addressed to Dr. Harry Ischiropoulos, Stokes Research Institute, Children's Hospital of Philadelphia, 416D Abramson Research Center, 3517 Civic Center Boulevard, Philadelphia, PA 19104-4318. Email: ischirop{at}mail.med.upenn.edu


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L. Chen, Y. Ding, B. Cagniard, A. D. Van Laar, A. Mortimer, W. Chi, T. G. Hastings, U. J. Kang, and X. Zhuang
Unregulated Cytosolic Dopamine Causes Neurodegeneration Associated with Oxidative Stress in Mice
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J. R. Mazzulli, M. Armakola, M. Dumoulin, I. Parastatidis, and H. Ischiropoulos
Cellular Oligomerization of {alpha}-Synuclein Is Determined by the Interaction of Oxidized Catechols with a C-terminal Sequence
J. Biol. Chem., October 26, 2007; 282(43): 31621 - 31630.
[Abstract] [Full Text] [PDF]


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