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J. Biol. Chem., Vol. 280, Issue 18, 17725-17731, May 6, 2005

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Inhibition of Chaperone Activity Is a Shared Property of Several Cu,Zn-Superoxide Dismutase Mutants That Cause Amyotrophic Lateral Sclerosis^*

Hemachand Tummala, Cheolwha Jung, Ashutosh Tiwari¶, Cynthia M. J. Higgins||, Lawrence J. Hayward**, and Zuoshang Xu**

From the Departments of Biochemistry and Molecular Pharmacology, Neurology, and Cell Biology and the ^**Neuroscience Program, University of Massachusetts Medical School, Worcester, Massachusetts 01605

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive motor neuron degeneration, paralysis, and death. Mutant Cu,Zn-superoxide dismutase (SOD1) causes a subset of ALS by an unidentified toxic property. Increasing evidence suggests that chaperone dysfunction plays a role in motor neuron degeneration in ALS. To investigate the relationship between mutant SOD1 expression and chaperone dysfunction, we measured chaperone function in central nervous system tissue lysates from normal mice and transgenic mice expressing human SOD1 variants. We observed a significant decrease in chaperone activity in tissues from mice expressing ALS-linked mutant SOD1 but not control mice expressing human wild type SOD1. This decrease was detected only in the spinal cord, became apparent by 60 days of age (before the onset of muscle weakness and significant motor neuron loss), and persisted throughout the late stages. In addition, this impairment of chaperone activity occurred only in cytosolic but not in mitochondrial and nuclear fractions. Furthermore, multiple recombinant human SOD1 mutants with differing biochemical and biophysical properties inhibited chaperone function in a cell-free extract of normal mouse spinal cords. Thus, mutant SOD1 proteins may impair chaperone function independent of gene expression in vivo, and this inhibition may be a shared property of ALS-linked mutant SOD1 proteins.

Received for publication, February 14, 2005

^* This work was supported by NINDS, National Institutes of Health Grant RO1 NS41739, the Amyotrophic Lateral Sclerosis (ALS) Association, and The Robert Packard Center for ALS Research at Johns Hopkins (to Z. X.), and NINDS, National Institutes of Health Grant R01 NS44170, the ALS Association, and the Muscular Dystrophy Association (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–S4.

^¶ Supported by an ALS Association fellowship.

^|| Supported by a National Institutes of Health post-doctoral fellowship.

To whom correspondence should be addressed: Dept. of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, 364 Plantation St., Worcester, MA 01605. Tel.: 508-856-3309; Fax: 508-856-2003; E-mail: zuoshang.xu{at}umassmed.edu.

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