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J. Biol. Chem., Vol. 282, Issue 32, 23465-23472, August 10, 2007

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Stabilization of Hyperdynamic Microtubules Is Neuroprotective in Amyotrophic Lateral Sclerosis^*

Patrizia Fanara¹, Jayee Banerjee, Rommel V. Hueck, Macha R. Harper, Mohamad Awada, Holly Turner, Kristofor H. Husted, Roland Brandt, and Marc K. Hellerstein^¶||

From the KineMed, Inc., Emeryville, California 94608, the Department of Neurobiology, University of Osnabrück, Barbarastrasse 11, Osnabrück 49076, Germany, the ^¶Department of Nutritional Sciences and Toxicology, University of California, Berkeley, California 94720, and the ^||Department of Medicine, University of California, San Francisco General Hospital, San Francisco, California 94110

Mutations in copper/zinc superoxide dismutase 1 (SOD1), a genetic cause of human amyotrophic lateral sclerosis, trigger motoneuron death through unknown toxic mechanisms. We report that transgenic SOD1G93A mice exhibit striking and progressive changes in neuronal microtubule dynamics from an early age, associated with impaired axonal transport. Pharmacologic administration of a microtubule-modulating agent alone or in combination with a neuroprotective drug to symptomatic SOD1G93A mice reduced microtubule turnover, preserved spinal cord neurons, normalized axonal transport kinetics, and delayed the onset of symptoms, while prolonging life by up to 26%. The degree of reduction of microtubule turnover was highly predictive of clinical responses to different treatments. These data are consistent with the hypothesis that hyperdynamic microtubules impair axonal transport and accelerate motor neuron degeneration in amyotrophic lateral sclerosis. Measurement of microtubule dynamics in vivo provides a sensitive biomarker of disease activity and therapeutic response and represents a new pharmacologic target in neurodegenerative disorders.

Received for publication, April 24, 2007 , and in revised form, June 8, 2007.

^* This work was supported in part by mice donated by Project A.L.S. 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 "Methods," references, and supplemental Figs. 6–10.

¹ To whom correspondence should be addressed: KineMed, Inc., 5980 Horton St., Ste. 400, Emeryville, CA 94608. Tel.: 510-655-6525; Fax: 510-655-6506; E-mail: pfanara{at}kinemed.com.

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