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J. Biol. Chem., Vol. 282, Issue 44, 32480-32490, November 2, 2007

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A Caspase-3-cleaved Fragment of the Glial Glutamate Transporter EAAT2 Is Sumoylated and Targeted to Promyelocytic Leukemia Nuclear Bodies in Mutant SOD1-linked Amyotrophic Lateral Sclerosis^*

Stuart L. Gibb, William Boston-Howes, Zeno S. Lavina^¶, Stefano Gustincich^¶1, Robert H. Brown, Jr.², Piera Pasinelli, and Davide Trotti³

From the Farber Institute for Neurosciences, Weinberg Unit for ALS Research, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, the Cecil B. Day Laboratory for Neuromuscular Research, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129, and ^¶Scuola Internazionale Studi Superiori Avanzati, Sector of Neurobiology, The Giovanni Armenise-Harvard Foundation Laboratory, AREA Science Park, 34012 Basovizza, Italy

EAAT2 (excitatory amino acid transporter 2) is a high affinity, Na⁺-dependent glutamate transporter of glial origin that is essential for the clearance of synaptically released glutamate and prevention of excitotoxicity. During the course of human amyotrophic lateral sclerosis (ALS) and in a transgenic mutant SOD1 mouse model of the disease, expression and activity of EAAT2 is remarkably reduced. We previously showed that some of the mutant SOD1 proteins exposed to oxidative stress inhibit EAAT2 by triggering caspase-3 cleavage of EAAT2 at a single defined locus. This gives rise to two fragments that we termed truncated EAAT2 and COOH terminus of EAAT2 (CTE). In this study, we report that analysis of spinal cord homogenates prepared from mutant G93A-SOD1 mice reveals CTE to be of a higher molecular weight than expected because it is conjugated with SUMO-1. The sumoylated CTE fragment (CTE-SUMO-1) accumulates in the spinal cord of these mice as early as presymptomatic stage (70 days of age) and not in other central nervous system areas unaffected by the disease. The presence and accumulation of CTE-SUMO-1 is specific to ALS mice, since it does not occur in the R6/2 mouse model for Huntington disease. Furthermore, using an astroglial cell line, primary culture of astrocytes, and tissue samples from G93A-SOD1 mice, we show that CTE-SUMO-1 is targeted to promyelocytic leukemia nuclear bodies. Since one of the proposed functions of promyelocytic leukemia nuclear bodies is regulation of gene transcription, we suggest a possible novel mechanism by which the glial glutamate transporter EAAT2 could contribute to the pathology of ALS.

Received for publication, May 25, 2007 , and in revised form, September 4, 2007.

^* This work was supported in part by National Institutes of Health Grant RO1-NS44292 (to D. T.), the Muscular Dystrophy Association (to D. T.), and the ALS Association (to D. T. and P. P.). The Weinberg Unit for ALS Research was also supported by the Farber Family Foundation. 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.

¹ Supported by Telethon Italia Grant GGP06268, GRAND, and the "Giovanni Armenise-Harvard Foundation."

² Supported by NINDS, National Institutes of Health, the ALS Association, Project ALS, the de Bourgknecht ALS Research Fund, the Angel Fund, the Al-Athel ALS Research Foundation, and the ALS Therapy Alliance.

³ To whom correspondence should be addressed: Farber Institute for the Neurosciences, Weinberg Unit for ALS Research, Thomas Jefferson University, 900 Walnut St., Philadelphia, PA 19107. Tel.: 215-955-8416; Fax: 215-503-9128; E-mail: davide.trotti{at}jefferson.edu.

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