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J. Biol. Chem., Vol. 282, Issue 15, 11068-11077, April 13, 2007

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p62 Accumulates and Enhances Aggregate Formation in Model Systems of Familial Amyotrophic Lateral Sclerosis^*

Jozsef Gal¹, Anna-Lena Ström¹, Renee Kilty, Fujian Zhang, and Haining Zhu²

From the Department of Molecular and Cellular Biochemistry and the Graduate Center for Nutritional Sciences, University of Kentucky, Lexington, Kentucky 40536

Amyotrophic lateral sclerosis (ALS) is a progressive neurode-generative disease characterized by motor neuron death. A hallmark of the disease is the appearance of protein aggregates in the affected motor neurons. We have found that p62, a protein implicated in protein aggregate formation, accumulated progressively in the G93A mouse spinal cord. The accumulation of p62 was in parallel to the increase of polyubiquitinated proteins and mutant SOD1 aggregates. Immunostaining studies showed that p62, ubiquitin, and mutant SOD1 co-localized in the protein aggregates in affected cells in G93A mouse spinal cord. The p62 protein selectively interacted with familial ALS mutants, but not WT SOD1. When p62 was co-expressed with SOD1 in NSC34 cells, it greatly enhanced the formation of aggregates of the ALS-linked SOD1 mutants, but not wild-type SOD1. Cell viability was measured in the presence and absence of overexpressed p62, and the results suggest that the large aggregates facilitated by p62 were not directly toxic to cells under the conditions in this study. Deletion of the ubiquitin-association (UBA) domain of p62 significantly decreased the p62-facilitated aggregate formation, but did not completely inhibit it. Further protein interaction experiments also showed that the truncated p62 with the UBA domain deletion remained capable of interacting with mutant SOD1. The findings of this study show that p62 plays a critical role in forming protein aggregates in familial ALS, likely by linking misfolded mutant SOD1 molecules and other cellular proteins together.

Received for publication, September 12, 2006 , and in revised form, February 7, 2007.

^* This work was supported in part by the University of Kentucky College of Medicine (start-up funds to H. Z.) and National Institutes of Health Grant R01-NS49126 (to H. Z.). 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 These authors made equal contributions.

² To whom correspondence should be addressed: Dept. of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, 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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