Regulation of Intracellular Copper by Induction of Endogenous Metallothioneins Improves the Disease Course in a Mouse Model of Amyotrophic Lateral Sclerosis

Neurotherapeutics : the Journal of the American Society for Experimental NeuroTherapeutics
Eiichi TokudaShin-Ichi Ono

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 (SOD1(G93A)). 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 SOD1(G93A) 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 SOD1(G93A) 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 SOD1(G93A) mice. In conclusion, the upregulation of endogenous MTs represents a promising strategy for the treatment of ALS linked to mutant SOD1.

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Citations

May 3, 2016·International Journal of Molecular Sciences·Eiichi Tokuda, Yoshiaki Furukawa
Jun 10, 2017·Expert Reviews in Molecular Medicine·Francisco J Gil-BeaAinara Vallejo-Illarramendi
Nov 9, 2017·Chemical Society Reviews·Elena Atrián-BlascoPeter Faller
Jul 3, 2018·Biological & Pharmaceutical Bulletin·Shinsuke NakamuraHideaki Hara
Sep 27, 2018·Metallomics : Integrated Biometal Science·K KyseniusP J Crouch
Mar 3, 2018·Cell Death & Disease·Sahar SheykhansariAjay Vikram Singh
Apr 20, 2017·Frontiers in Neuroscience·Yuho OkitaDean L Pountney
Aug 23, 2018·Frontiers in Neuroscience·Rossana SirabellaGiuseppe Pignataro
Aug 18, 2018·Journal of Nutrition and Metabolism·Acsa Nara A B BarrosLucia Leite-Lais

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