Mutation-dependent Polymorphism of Cu,Zn-Superoxide Dismutase Aggregates in the Familial Form of Amyotrophic Lateral Sclerosis*
- From the ‡Laboratory for Structural Neuropathology and
- §Laboratory for Motor Neuron Disease, RIKEN Brain Science Institute, Wako, Saitama 351-0198, Japan
- 1 To whom correspondence may be addressed: 3-14-1 Hiyoshi, Kohoku, Yokohama 223-8522, Japan. Fax: 81-45-566-1697; E-mail: furukawa{at}chem.keio.ac.jp.
- 3 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.
Abstract
More than 100 different mutations in Cu,Zn-superoxide dismutase (SOD1) are linked to a familial form of amyotrophic lateral sclerosis (fALS). Pathogenic mutations facilitate fibrillar aggregation of SOD1, upon which significant structural changes of SOD1 have been assumed; in general, however, a structure of protein aggregate remains obscure. Here, we have identified a protease-resistant core in wild-type as well as fALS-causing mutant SOD1 aggregates. Three different regions within an SOD1 sequence are found as building blocks for the formation of an aggregate core, and fALS-causing mutations modulate interactions among these three regions to form a distinct core, namely SOD1 aggregates exhibit mutation-dependent structural polymorphism, which further regulates biochemical properties of aggregates such as solubility. Based upon these results, we propose a new pathomechanism of fALS in which mutation-dependent structural polymorphism of SOD1 aggregates can affect disease phenotypes.
- Amyloid
- Amyotropic Lateral Sclerosis (Lou Gehrig Disease)
- Protein Folding
- Protein-Protein Interactions
- Superoxide Dismutase (SOD)
- Protein Aggregation
Footnotes
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↵* This work was supported by Grant-in-aid for Scientific Research on Priority Areas (Research on Pathomechanisms of Brain Disorders) 17025044 (to N. N.), Grants-in-aid 20770130 (to Y. F.) and 21390274 (to K. Y.) from the Ministry of Education, Culture, Sports, Science and Technology of Japan, and a Health and Labour Science Research grant (to K. Y.).
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The on-line version of this article (available at http://www.jbc.org) contains supplemental Table 1 and Figs. S1–S4.
- Received February 11, 2010.
- Revision received April 16, 2010.
- © 2010 by The American Society for Biochemistry and Molecular Biology, Inc.
