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J. Biol. Chem., Vol. 281, Issue 44, 33325-33335, November 3, 2006

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Insoluble Mutant SOD1 Is Partly Oligoubiquitinated in Amyotrophic Lateral Sclerosis Mice^*

Manuela Basso, Tania Massignan, Giuseppina Samengo, Cristina Cheroni^¶, Silvia De Biasi^||, Mario Salmona, Caterina Bendotti^¶, and Valentina Bonetto, Assistant Telethon Scientist¹

From the Dulbecco Telethon Institute, Milan, Italy, the Department of Molecular Biochemistry and Pharmacology, Mario Negri Institute for Pharmacological Research, 20157 Milan, Italy, the ^¶Department of Neuroscience, Mario Negri Institute for Pharmacological Research, 20157 Milan, Italy, and the ^||Department of Biomolecular Sciences and Biotechnology, University of Milan, 20133 Milan, Italy

Mutations in the Cu,Zn-superoxide dismutase (SOD1) gene cause a familial form of amyotrophic lateral sclerosis (ALS) through an unknown gain-of-function mechanism. Mutant SOD1 aggregation may be the toxic property. In fact, proteinaceous inclusions rich in mutant SOD1 have been found in tissues from the familial form of ALS patients and in mutant SOD1 animals, before disease onset. However, very little is known of the constituents and mechanism of formation of aggregates in ALS. We and others have shown that there is a progressive accumulation of detergent-insoluble mutant SOD1 in the spinal cord of G93A SOD1 mice. To investigate the mechanism of SOD1 aggregation, we characterized by proteome technologies SOD1 isoforms in a Triton X-100-insoluble fraction of spinal cord from G93A SOD1 mice at different stages of the disease. This showed that at symptomatic stages of the disease, part of the insoluble SOD1 is unambiguously mono- and oligoubiquitinated, in spinal cord and not in hippocampus, and that ubiquitin branches at Lys⁴⁸, the major signal for proteasome degradation. At presymptomatic stages of the disease, only insoluble unmodified SOD1 is recovered. Partial ubiquitination of SOD1-rich inclusions was also confirmed by immunohistochemical and electron microscopy analysis of lumbar spinal cord sections from symptomatic G93A SOD1 mice. On the basis of these results, we propose that ubiquitination occurs only after SOD1 aggregation and that oligoubiquitination may underline alternative mechanisms in disease pathogenesis.

Received for publication, April 11, 2006 , and in revised form, August 4, 2006.

^* This work was supported by grants from the Telethon Foundation (to V. B., C. B., and S. D. B.), the Cariplo Foundation (to V. B. and M. S.), and the Compagnia San Paolo Foundation (to V. B.) and Italian Ministry for University and Research Protocol RBNE0185www_08 (to C. B.). 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 To whom correspondence should be addressed: Dulbecco Telethon Institute and Mario Negri Institute for Pharmacological Research, Via Eritrea 62, 20157 Milan, Italy. Tel.: 390239014548; Fax: 39023546277; E-mail: bonetto{at}marionegri.it.

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