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J. Biol. Chem., Vol. 283, Issue 35, 24167-24176, August 29, 2008

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Complete Loss of Post-translational Modifications Triggers Fibrillar Aggregation of SOD1 in the Familial Form of Amyotrophic Lateral Sclerosis^*

Yoshiaki Furukawa¹, Kumi Kaneko, Koji Yamanaka, Thomas V. O'Halloran^¶, and Nobuyuki Nukina²

From the Laboratory for Structural Neuropathology, Yamanaka Research Unit, RIKEN Brain Science Institute, Wako, Saitama 351-0198, Japan and ^¶Chemistry of Life Processes Institute, Northwestern University, Evanston, Illinois 60208-3113

Dominant mutations in Cu,Zn-superoxide dismutase (SOD1) cause a familial form of amyotrophic lateral sclerosis (fALS), and aggregation of mutant SOD1 has been proposed to play a role in neurodegeneration. A growing body of evidence suggests that fALS-causing mutations destabilize the native structure of SOD1, leading to aberrant protein interactions for aggregation. SOD1 becomes stabilized and enzymatically active after copper and zinc binding and intramolecular disulfide formation, but it remains unknown which step(s) in the SOD1 maturation process is important in the pathological aggregation. In this study we have shown that apoSOD1 without disulfide is the most facile state for formation of amyloid-like fibrillar aggregates. fALS mutations impair either zinc binding, disulfide formation, or both, leading to accumulation of the aggregation-prone, apo, and disulfide-reduced SOD1. Moreover, we have found that the copper chaperone for SOD1 (CCS) facilitates maturation of SOD1 and that CCS overexpression ameliorates intracellular aggregation of mutant SOD1 in vivo. Based on our in vivo and in vitro results, we propose that facilitation of post-translational modifications is a promising strategy to reduce SOD1 aggregation in the cell.

Received for publication, March 17, 2008 , and in revised form, May 13, 2008.

^* This work was supported by Grant-in-aid 17025044 for Scientific Research on Priority Areas Research on Pathomechanisms of Brain Disorders (to N. N.) and Grants-in-aid 18031044 and 18770143 (to Y. F.) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan, a grant-in-aid for the Research on Measures for Intractable Diseases from the Ministry of Health, Welfare, and Labor, Japan (to N. N.), and by the Nakabayashi Trust for ALS Research (to Y. F.). 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. 1-5 and Text 1.

¹ To whom correspondence may be addressed: 2-1 Hirosawa, Wako, Saitama 351-0198, Japan. Fax: 81-48-462-4796; E-mail: furukawa{at}brain.riken.jp.

² To whom correspondence may be addressed: 2-1 Hirosawa, Wako, Saitama 351-0198, Japan. Fax: 81-48-462-4796; E-mail: nukina{at}brain.riken.jp.

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