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J. Biol. Chem., Vol. 280, Issue 16, 16295-16304, April 22, 2005

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Protein Nitration in a Mouse Model of Familial Amyotrophic Lateral Sclerosis

POSSIBLE MULTIFUNCTIONAL ROLE IN THE PATHOGENESIS^*

Filippo Casoni, Manuela Basso, Tania Massignan, Elisabetta Gianazza¶, Cristina Cheroni, Mario Salmona, Caterina Bendotti, and Valentina Bonetto, An Assistant Telethon Scientist||

From the Dulbecco Telethon Institute, Milan, Italy, the "Mario Negri" Institute for Pharmacological Research, Milan 20157, Italy, and the ^¶Proteomics and Protein Structure Study Group and CEND, Department of Pharmacological Sciences, University of Milan, Milan 20133, Italy

Multiple mechanisms have been proposed to contribute to amyotrophic lateral sclerosis (ALS) pathogenesis, including oxidative stress. Early evidence of a role for oxidative damage was based on the finding, in patients and murine models, of high levels of markers, such as free nitrotyrosine (NT). However, no comprehensive study on the protein targets of nitration in ALS has been reported. We found an increased level of NT immunoreactivity in spinal cord protein extracts of a transgenic mouse model of familial ALS (FALS) at a presymptomatic stage of the disease compared with age-matched controls. NT immunoreactivity is increased in the soluble fraction of spinal cord homogenates and is found as a punctate staining in motor neuron perikarya of presymptomatic FALS mice. Using a proteome-based strategy, we identified proteins nitrated in vivo, under physiological or pathological conditions, and compared their level of specific nitration. - and -enolase, ATP synthase chain, and heat shock cognate 71-kDa protein and actin were overnitrated in presymptomatic FALS mice. We identified by matrix-assisted laser desorption/ionization mass spectrometry 16 sites of nitration in proteins oxidized in vivo. In particular, -enolase nitration at Tyr⁴³, target also of phosphorylation, brings additional evidence on the possible interference of nitration with phosphorylation. In conclusion, we propose that protein nitration may have a role in ALS pathogenesis, acting directly by inhibiting the function of specific proteins and indirectly interfering with protein degradation pathways and phosphorylation cascades.

Received for publication, November 19, 2004 , and in revised form, February 4, 2005.

^* This work was supported by Telethon Foundation Grant TCP01010(to V. B.), Cariplo Foundation Grant S01010FCRA (to V. B.), and Italian Ministry of the University and Research (FIRB Negoziali) Protocol RBNEO1B5WW_008. 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. Tel.: 39-0239014548; Fax: 39-023546277; E-mail: bonetto{at}marionegri.it.

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