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J. Biol. Chem., Vol. 279, Issue 51, 52984-52990, December 17, 2004

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-Synuclein Expression Levels Do Not Significantly Affect Proteasome Function and Expression in Mice and Stably Transfected PC12 Cell Lines^*

Begoña Martìn-Clemente, Beatriz Alvarez-Castelao¶, Isabel Mayo||, Ana Belén Sierra, Virginia Dìaz, Miguel Milán**, Isabel Fariñas**, Teresa Gómez-Isla, Isidro Ferrer, and José G. Castaño¶¶

From the Departamento de Bioquìmica e Instituto de Investigaciones Biomédicas "Alberto Sols," Universidad Autónoma de Madrid-Consejo Superior de Investigaciones Cientìfica, Facultad de Medicina UAM, 28029 Madrid, Spain, the ^**Departamento de Biologìa Celular, Facultad de Biológicas, Universidad de Valencia, 46100 Valencia, Spain, the Departamento de Neurociencias, Clìnica Universitaria de Navarra, 31008 Pamplona, Spain, and the Instituto de Neuropatologìa, Servicio de Anatomìa Patológica, Hospital Universitario de Bellvitge, 08907 Hospitalet de Llobregat, Spain

-Synuclein (-syn) is a small protein of unknown function that is found aggregated in Lewy bodies, the histopathological hallmark of sporadic Parkinson disease and other synucleinopathies. Mutations in the -syn gene and a triplication of its gene locus have been identified in early onset familial Parkinson disease. -Syn turnover can be mediated by the proteasome pathway. A survey of published data may lead to the suggestion that overexpression of -syn wild type, and/or their variants (A53T and A30P), may produce a decrease in proteasome activity and function, contributing to -syn aggregation. To investigate the relationship between synuclein expression and proteasome function we have studied proteasome peptidase activities and proteasome subunit expression (, -constitutive, and inducible) in mice either lacking -syn (knock-out mice) or transgenic for human -syn A30P (under control of PrP promoter, at a time when no clear gliosis can be observed). Similar studies are presented in PC12 cells overexpressing enhanced yellow fluorescent protein fusion constructs of human wild type, A30P, and A53T -syn. In these cell lines we have also analyzed the assembly of 20 S proteasome complex and the degradation rate of a well known substrate of the proteasome pathway, Ib. Overall the data obtained led us to the conclusion that -synuclein expression levels by themselves have no significant effect on proteasome peptidase activity, subunit expression, and proteasome complex assembly and function. These results strengthen the suggestion that other mechanisms resulting in synuclein aggregation (not simply expression levels) may be the key to understand the possible effect of aggregated synuclein on proteasome function.

Received for publication, August 6, 2004 , and in revised form, September 24, 2004.

^* This work was supported by Comisión Interministerial de Ciencia y Tecnologìa (SAF2002-00566, GEN2001-4851) and CAM (08.5/0041/2002). 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.

Recipient of a Postdoctoral Fellowship from CAM.

^¶ Recipient of a Predoctoral Fellowship from MCYT;

^|| Recipient of a Predoctoral Fellowship from Fundación la Caixa.

^¶¶ To whom correspondence should be addressed. Fax: 34-91-585-4401; E-mail: joseg.castano{at}uam.es.

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