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Regulation of Intracellular Copper by Induction of Endogenous Metallothioneins Improves the Disease Course in a Mouse Model of Amyotrophic Lateral Sclerosis
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
2015 (English)In: Neurotherapeutics, ISSN 1933-7213, Vol. 12, no 2, 461-476 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2015. Vol. 12, no 2, 461-476 p.
Keyword [en]
Amyotrophic lateral sclerosis, Copper dyshomeostasis, Dexamethasone, Metallothioneins, Superoxide dismutase-1
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URN: urn:nbn:se:umu:diva-103742DOI: 10.1007/s13311-015-0346-xISI: 000353223000018PubMedID: 25761970OAI: diva2:815644
Available from: 2015-06-01 Created: 2015-05-28 Last updated: 2015-12-01Bibliographically approved

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Tokuda, Eiichi
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Clinical chemistry

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