Iron accumulation promotes TACE-mediated TNF-α secretion and neurodegeneration in a mouse model of ALS

• Published in: Neurobiology of disease Vol. 80; pp. 63 - 69
• Main Authors: Lee, Jae Keun, Shin, Jin Hee, Gwag, Byoung Joo, Choi, Eui-Ju
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.08.2015; Elsevier
• Subjects: ADAM Proteins - metabolism; ADAM17 Protein; ALS; Amyotrophic Lateral Sclerosis - genetics; Amyotrophic Lateral Sclerosis - metabolism; Amyotrophic Lateral Sclerosis - pathology; Animals; Disease Models, Animal; Humans; Iron; Iron - metabolism; Iron - toxicity; Mice; Mice, Transgenic; Motor Activity; Motor neuron death; Motor Neurons - metabolism; Motor Neurons - pathology; Neurology; Oxidative Stress - genetics; Reactive Oxygen Species - metabolism; Spinal Cord - metabolism; Spinal Cord - pathology; Superoxide Dismutase - genetics; TNF-α; TNF-α converting enzyme (TACE); Tumor Necrosis Factor-alpha - blood; ALS; Iron; TNF-α converting enzyme (TACE); TNF-α; Motor neuron death
• ISSN: 0969-9961; 1095-953X
• DOI: 10.1016/j.nbd.2015.05.009

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.