Regulation of Intracellular Copper by Induction of Endogenous Metallothioneins Improves the Disease Course in a Mouse Model of Amyotrophic Lateral Sclerosis |
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Authors: | Eiichi Tokuda Shunsuke Watanabe Eriko Okawa Shin-ichi Ono |
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Institution: | Laboratory of Clinical Medicine, School of Pharmacy, Nihon University, 7-7-1 Narashinodai, Funabashi, Chiba 274-8555 Japan ;Department of Medical Biosciences, Clinical Chemistry, Umeå University, Building 6M, 2nd Floor, Umeå, 901-85 Sweden ;Division of Neurology, Akiru Municipal Medical Center, 78-1 Hikida, Akiru, Tokyo, 197-0834 Japan |
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Abstract: | Mutations in SOD1 cause amyotrophic lateral sclerosis (ALS), an incurable motor neuron disease. The pathogenesis of the disease is poorly understood, but intracellular copper dyshomeostasis has been implicated as a key process in the disease. We recently observed that metallothioneins (MTs) are an excellent target for the modification of copper dyshomeostasis in a mouse model of ALS (SOD1G93A). Here, we offer a therapeutic strategy designed to increase the level of endogenous MTs. The upregulation of endogenous MTs by dexamethasone, a synthetic glucocorticoid, significantly improved the disease course and rescued motor neurons in SOD1G93A mice, even if the induction was initiated when peak body weight had decreased by 10 %. Neuroprotection was associated with the normalization of copper dyshomeostasis, as well as with decreased levels of SOD1G93A aggregates. Importantly, these benefits were clearly mediated in a MT-dependent manner, as dexamethasone did not provide any protection when endogenous MTs were abolished from SOD1G93A mice. In conclusion, the upregulation of endogenous MTs represents a promising strategy for the treatment of ALS linked to mutant SOD1.Electronic supplementary materialThe online version of this article (doi:10.1007/s13311-015-0346-x) contains supplementary material, which is available to authorized users. |
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Keywords: | Amyotrophic lateral sclerosis Copper dyshomeostasis Dexamethasone Metallothioneins Superoxide dismutase-1 |
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