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J. Biol. Chem., Vol. 279, Issue 45, 46915-46920, November 5, 2004

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-Synuclein Is Required for the Fibrillar Nature of Ubiquitinated Inclusions Induced by Proteasomal Inhibition in Primary Neurons^*

Hardy J. Rideout, Paula Dietrich, Qiaohong Wang, William T. Dauer, and Leonidas Stefanis¶||

From the Departments of Neurology and ^¶Pathology, Columbia University, New York, New York 10032 and ^||Neurobiology Laboratory, Foundation of Biomedical Research of the Academy of Athens, Athens 11527, Greece

Proteasomal dysfunction may underlie certain neuro-degenerative conditions such as Parkinson disease. We have shown that pharmacological inhibition of the proteasome in cultured neuronal cells leads to apoptotic death and formation of cytoplasmic ubiquitinated inclusions. These inclusions stain for -synuclein and assume a fibrillar structure, as assessed by thioflavine S staining, and therefore resemble Lewy bodies. -Synuclein is thought to be a central component of Lewy bodies. Whether -synuclein is required for inclusion formation or apoptotic death has not been formally assessed. The present study examines whether -synuclein deficiency in neurons alters their sensitivity to proteasomal inhibition-induced apoptosis or inclusion formation. Cortical neurons derived from -synuclein-null mice showed a similar sensitivity to death induced by the proteasomal inhibitor lactacystin compared with neurons derived from wild-type mice. Furthermore, the absence of -synuclein did not influence the percentage of lactacystin-treated neurons harboring cytoplasmic ubiquitinated inclusions or alter the solubility of such inclusions. In contrast, however, ubiquitinated inclusions in -synuclein-deficient neurons lacked amyloid-like fibrillization, as determined by thioflavine S staining. This indicates that although -synuclein deficiency does not affect the formation of ubiquitinated inclusions, it does significantly alter their structure. The lack of effect on survival in -synuclein knock-out cultures further suggests that the fibrillar nature of the inclusions does not contribute to neuronal degeneration in this model.

Received for publication, May 10, 2004 , and in revised form, August 16, 2004.

^* 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.

To whom correspondence should be addressed: Dept. of Neurology, Columbia University, Black Bldg., Rm. 326, 650 W. 168th St., New York, NY 10032. Tel.: 212-305-3415; Fax: 212-305-5450; E-mail: HR227{at}columbia.edu.

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