Intracellular amyloid beta interacts with SOD1 and impairs the enzymatic activity of SOD1: implications for the pathogenesis of amyotrophic lateral sclerosis.
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease caused by the degeneration of motor neurons. Mutations in Cu/Zn superoxide dismutase (SOD1), including G93A, were reportedly linked to familial ALS. SOD1 is a key antioxidant enzyme, and is also one of the major targets for oxidative damage in the brains of patients suffering from Alzheimers disease (AD). Several lines of evidence suggest that intracellular amyloid beta (Abeta) is associated with the pathogenesis of AD. In this report we demonstrate that intracellular Abeta directly interacts with SOD1, and that this interaction decreases the enzymatic activity of the enzyme. We observed Abeta-SOD1 aggregates in the perinuclear region of H4 cells, and mapped the SOD1 binding region to Abeta amino acids 26-42. Interestingly, intracellular Ab binds to the SOD1 G93A mutant with greater affinity than to wild-type SOD1. This resulted in considerably less mutant enzymatic activity. Our study implicates a potential role for Abeta in the development of ALS by interacting with the SOD1 G93A mutant.
Yoon
Eun Jin
EJ
School of Life Sciences and Biotechnology, Korea University, Seoul 136-701, Korea.
Park
Hyo Jin
HJ
Kim
Goo Young
GY
Cho
Hyung Min
HM
Choi
Jung Ha
JH
Park
Hye Yoon
HY
Jang
Ja Young
JY
Rhim
Hyang Shuk
HS
Kang
Seong Man
SM
D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism*; D000690:Amyotrophic Lateral Sclerosis / Q000201:enzymology*; D017209:Apoptosis; D002460:Cell Line; D045744:Cell Line, Tumor; D006801:Humans; D008969:Molecular Sequence Data; D017354:Point Mutation; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*; D000072105:Superoxide Dismutase-1
D016229:Amyloid beta-Peptides; C000606290:SOD1 protein, human; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1