title: Mutation-dependent polymorphism of Cu,Zn-superoxide dismutase aggregates in the familial form of amyotrophic lateral sclerosis.
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.
authors.affiliation: Laboratory for Structural Neuropathology, RIKEN Brain Science Institute, Wako, Saitama 351-0198, Japan. furukawa@chem.keio.ac.jp
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Furukawa
authors.forename: Kumi
authors.initials: K
authors.lastname: Kaneko
authors.forename: Koji
authors.initials: K
authors.lastname: Yamanaka
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Nukina
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000201:enzymology* / Q000235:genetics*; D000818:Animals; D001681:Biological Assay; D051379:Mice; D008958:Models, Molecular; D050505:Mutant Proteins / Q000737:chemistry / Q000235:genetics / Q000648:ultrastructure; D009154:Mutation / Q000235:genetics*; D011110:Polymorphism, Genetic; D020836:Protein Structure, Quaternary; D012521:Sarcosine / Q000031:analogs & derivatives / Q000494:pharmacology; D012995:Solubility / Q000187:drug effects; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013482:Superoxide Dismutase / Q000737:chemistry* / Q000235:genetics* / Q000648:ultrastructure
chemical_list: D050505:Mutant Proteins; C025231:sarkosyl; D013482:Superoxide Dismutase; D012521:Sarcosine
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