Mutation-dependent Polymorphism of Cu,Zn-Superoxide Dismutase Aggregates in the Familial Form of Amyotrophic Lateral Sclerosis

• Published in: The Journal of biological chemistry Vol. 285; no. 29; pp. 22221 - 22231
• Main Authors: Furukawa, Yoshiaki, Kaneko, Kumi, Yamanaka, Koji, Nukina, Nobuyuki
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 16.07.2010; American Society for Biochemistry and Molecular Biology
• Subjects: Amyloid; Amyotrophic Lateral Sclerosis - enzymology; Amyotrophic Lateral Sclerosis - genetics; Amyotropic Lateral Sclerosis (Lou Gehrig Disease); Animals; Biological Assay; Mice; Models, Molecular; Molecular Bases of Disease; Mutant Proteins - chemistry; Mutant Proteins - genetics; Mutant Proteins - ultrastructure; Mutation - genetics; Polymorphism, Genetic; Protein Aggregation; Protein Folding; Protein Structure and Folding; Protein Structure, Quaternary; Protein-Protein Interactions; Sarcosine - analogs & derivatives; Sarcosine - pharmacology; Solubility - drug effects; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Superoxide Dismutase (SOD); Superoxide Dismutase - chemistry; Superoxide Dismutase - genetics; Superoxide Dismutase - ultrastructure; Amyotropic Lateral Sclerosis (Lou Gehrig Disease); Amyloid; Superoxide Dismutase (SOD); Protein Aggregation; Protein Folding; Protein-Protein Interactions
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M110.113597

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.