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J. Biol. Chem., Vol. 282, Issue 22, 16691-16699, June 1, 2007

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Interaction between Familial Amyotrophic Lateral Sclerosis (ALS)-linked SOD1 Mutants and the Dynein Complex^*

Fujian Zhang¹, Anna-Lena Ström¹, Kei Fukada, Sangmook Lee^¶, Lawrence J. Hayward^¶, and Haining Zhu²

From the Graduate Center for Nutritional Sciences, Department of Molecular and Cellular Biochemistry, College of Medicine, Lexington, Kentucky 40536 and the ^¶Department of Neurology, University of Massachusetts Medical School, Worcester, Massachusetts 01655

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by progressive motor neuron death. More than 90 mutations in the copper-zinc superoxide dismutase (SOD1) gene cause a subset of familial ALS. Toxic properties have been proposed for the ALS-linked SOD1 mutants, but the nature of the toxicity has not been clearly specified. Cytoplasmic inclusion bodies containing mutant SOD1 and a number of other proteins are a pathological hallmark of mutant SOD1-mediated familial ALS, but whether such aggregates are toxic to motor neurons remains unclear. In this study, we identified a dynein subunit as a component of the mutant SOD1-containing high molecular weight complexes using proteomic techniques. We further demonstrated interaction and colocalization between dynein and mutant SOD1, but not normal SOD1, in cultured cells and also in G93A and G85R transgenic rodent tissues. Moreover, the interaction occurred early, prior to the onset of symptoms in the ALS animal models and increased over the disease progression. Motor neurons with long axons are particularly susceptible to defects in axonal transport. Our results demonstrate a direct "gain-of-interaction" between mutant SOD1 and dynein, which may provide insights into the mechanism by which mutant SOD1 could contribute to a defect in retrograde axonal transport or other dynein functions. The aberrant interaction is potentially critical to the formation of mutant SOD1 aggregates as well as the toxic cascades leading to motor neuron degeneration in ALS.

Received for publication, October 17, 2006 , and in revised form, February 26, 2007.

^* This work was supported in part by the University of Kentucky College of Medicine (start-up funds to H. Z.), National Institutes of Health Grants R21-ES12025 and R01-NS49126 (to H. Z.) and R01-NS44170 (to L. J. H.), the ALS Association (to L. J. H.), the Muscular Dystrophy Association (to L. J. H.), and the ALS Therapy Alliance (to L. J. H.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1 and S2.

¹ Both authors contributed equally to the results of this work.

² To whom correspondence should be addressed: 741 South Limestone St., Lexington, KY 40536. Tel.: 859-323-3643; Fax: 859-257-2283; E-mail: haining{at}uky.edu.

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