Complete loss of post-translational modifications triggers fibrillar aggregation of SOD1 in the familial form of amyotrophic lateral sclerosis.
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.
Laboratory for Structural Neuropathology, Yamanaka Research Unit, RIKEN Brain Science Institute, Wako, Saitama, Japan.
Yoshiaki
Y
Furukawa
Kumi
K
Kaneko
Koji
K
Yamanaka
Thomas V
TV
O'Halloran
Nobuyuki
N
Nukina
D000690:Amyotrophic Lateral Sclerosis / Q000201:enzymology* / Q000235:genetics; D000818:Animals; D002460:Cell Line; D003300:Copper / Q000378:metabolism; D004220:Disulfides / Q000378:metabolism; D030342:Genetic Diseases, Inborn / Q000201:enzymology* / Q000235:genetics; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D046188:Protein Modification, Translational / Q000235:genetics; D017434:Protein Structure, Tertiary / Q000235:genetics; D013482:Superoxide Dismutase / Q000096:biosynthesis* / Q000235:genetics; D000072105:Superoxide Dismutase-1; D015032:Zinc / Q000378:metabolism
C114678:CCS protein, human; D004220:Disulfides; D018832:Molecular Chaperones; C000606290:SOD1 protein, human; D003300:Copper; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D015032:Zinc