title: Iron accumulation promotes TACE-mediated TNF-α secretion and neurodegeneration in a mouse model of ALS.
abstract: Oxidative stress contributes to degeneration of motor neurons in patients with amyotrophic lateral sclerosis (ALS) as well as transgenic mice overexpressing ALS-associated human superoxide dismutase 1 (SOD1) mutants. However, the molecular mechanism by which the ALS-linked SOD1 mutants including SOD1(G93A) induce oxidative stress remains unclear. Here, we show that iron was accumulated in ventral motor neurons from SOD1(G93A)-transgenic mice even at 4 weeks of age, subsequently inducing oxidative stress. Iron chelation with deferoxamine mesylate delayed disease onset and extended lifespan of SOD1(G93A) mice. Furthermore, SOD1(G93A)-induced iron accumulation mediated the increase in the enzymatic activity of TNF-α converting enzyme (TACE), leading to secretion of TNF-α at least in part through iron-dependent oxidative stress. Our findings suggest iron as a key determinant of early motor neuron degeneration as well as proinflammatory responses at symptomatic stage in SOD1(G93A) mice.
authors.affiliation: Laboratory of Cell Death and Human Diseases, Department of Life Sciences, School of Life Sciences and Biotechnology, Korea University, Seoul, Republic of Korea.
authors.forename: Jae Keun
authors.initials: JK
authors.lastname: Lee
authors.affiliation: Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
authors.forename: Jin Hee
authors.initials: JH
authors.lastname: Shin
authors.affiliation: GNT Pharma, Suwon, Republic of Korea.
authors.forename: Byoung Joo
authors.initials: BJ
authors.lastname: Gwag
authors.affiliation: Laboratory of Cell Death and Human Diseases, Department of Life Sciences, School of Life Sciences and Biotechnology, Korea University, Seoul, Republic of Korea. Electronic address: ejchoi@korea.ac.kr.
authors.forename: Eui-Ju
authors.initials: EJ
authors.lastname: Choi
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism*; D000072198:ADAM17 Protein; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D004195:Disease Models, Animal; D006801:Humans; D007501:Iron / Q000378:metabolism / Q000633:toxicity*; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity; D009046:Motor Neurons / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology; D013482:Superoxide Dismutase / Q000235:genetics*; D014409:Tumor Necrosis Factor-alpha / Q000097:blood*
chemical_list: D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D007501:Iron; C109415:SOD1 G93A protein; D013482:Superoxide Dismutase; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; C000606463:Adam17 protein, mouse
keywords: ALS; Iron; Motor neuron death; TNF-α; TNF-α converting enzyme (TACE)