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Originally published In Press as doi:10.1074/jbc.M310994200 on November 19, 2003

J. Biol. Chem., Vol. 279, Issue 6, 4625-4631, February 6, 2004
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Aggresomes Formed by {alpha}-Synuclein and Synphilin-1 Are Cytoprotective*

Mikiei Tanaka{ddagger}, Yong Man Kim{ddagger}§, Gwang Lee{ddagger}, Eunsung Junn{ddagger}||, Takeshi Iwatsubo**, and M. Maral Mouradian, William Dow Lovett Professor of Neurology{ddagger}||{ddagger}{ddagger}

From the {ddagger}Genetic Pharmacology Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892-1406, ||Department of Neurology, University of Medicine and Dentistry of New Jersey/Robert Wood Johnson Medical School, Piscataway, New Jersey 08854, and **Department of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan

Lewy bodies (LBs), which are the hallmark pathologic features of Parkinson's disease and of dementia with LBs, have several morphologic and molecular similarities to aggresomes. Whether such cytoplasmic inclusions contribute to neuronal death or protect cells from the toxic effects of misfolded proteins remains controversial. In this report, the role of aggresomes in cell viability was addressed in the context of over-expressing {alpha}-synuclein and its interacting partner synphilin-1 using engineered 293T cells. Inhibition of proteasome activity elicited the formation of juxtanuclear aggregates with characteristics of aggresomes including immunoreactivity for vimentin, {gamma}-tubulin, ubiquitin, proteasome subunit, and hsp70. As expected from the properties of aggresomes, the microtubule disrupting agents, vinblastin and nocodazole, markedly prevented the formation of these inclusions. Similar to LBs, the phosphorylated form of {alpha}-synuclein co-localized in these synphilin-1-containing aggresomes. Although the caspase inhibitor z-VAD-fmk significantly reduced the number of apoptotic cells, it had no impact on the percentage of aggresome-positive cells. Finally, quantitative analysis revealed aggresomes in 60% of nonapoptotic cells but only in 10% of apoptotic cells. Additionally, {alpha}-synuclein-induced apoptosis was not coupled with increased prevalence of aggresome-bearing cells. Taken together, these observations indicate a disconnection between aggresome formation and apoptosis, and support a protective role for these inclusions from the toxicity associated with the combined over-expression of {alpha}-synuclein and synphilin-1.

Received for publication, October 6, 2003 , and in revised form, November 18, 2003.

* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ Present address: Dept. of Parasitology, College of Medicine, Wonkwang University, Iksan, Jeonbuk 570-749, Korea.

Present address: Laboratory of Medical Genetics, Institute for Medical Sciences, Ajou University School of Medicine, Wonchon-Dong, Paldal-Gu, Suwon 442-721, Korea.

{ddagger}{ddagger} To whom correspondence should be addressed: Dept. of Neurology, UMDNJ/Robert Wood Johnson Medical School, 683 Hoes Lane, Room 180, Piscataway, NJ 08854. Tel.: 732-235-4772; Fax: 732-235-4773; E-mail: Mouradian{at}umdnj.edu.


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