Iron accumulation promotes TACE-mediated TNF-alpha secretion and neurodegeneration in a mouse model of ALS
- Authors
- Lee, Jae Keun; Shin, Jin Hee; Gwag, Byoung Joo; Choi, Eui-Ju
- Issue Date
- 8월-2015
- Publisher
- ACADEMIC PRESS INC ELSEVIER SCIENCE
- Keywords
- ALS; Iron; Motor neuron death; TNF-alpha; TNF-alpha converting enzyme (TACE)
- Citation
- NEUROBIOLOGY OF DISEASE, v.80, pp.63 - 69
- Indexed
- SCIE
SCOPUS
- Journal Title
- NEUROBIOLOGY OF DISEASE
- Volume
- 80
- Start Page
- 63
- End Page
- 69
- URI
- https://scholar.korea.ac.kr/handle/2021.sw.korea/92795
- DOI
- 10.1016/j.nbd.2015.05.009
- ISSN
- 0969-9961
- 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-alpha converting enzyme (TACE), leading to secretion of TNF-alpha 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. (C) 2015 Elsevier Inc. All rights reserved.
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