title: Regulation of Intracellular Copper by Induction of Endogenous Metallothioneins Improves the Disease Course in a Mouse Model of Amyotrophic Lateral Sclerosis.
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.
authors.affiliation: Laboratory of Clinical Medicine, School of Pharmacy, Nihon University, 7-7-1 Narashinodai, Funabashi, Chiba, 274-8555, Japan.
authors.forename: Eiichi
authors.initials: E
authors.lastname: Tokuda
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Watanabe
authors.forename: Eriko
authors.initials: E
authors.lastname: Okawa
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Ono
mesh_terms: D000367:Age Factors; D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D039481:CD11b Antigen / Q000378:metabolism; D003300:Copper / Q000378:metabolism*; D003907:Dexamethasone / Q000627:therapeutic use*; D004195:Disease Models, Animal; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006801:Humans; D008054:Lipid Peroxides / Q000378:metabolism; D008668:Metallothionein / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D013116:Spinal Cord / Q000473:pathology; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D015854:Up-Regulation / Q000187:drug effects* / Q000235:genetics
chemical_list: D000893:Anti-Inflammatory Agents; D039481:CD11b Antigen; D005904:Glial Fibrillary Acidic Protein; D008054:Lipid Peroxides; D020033:Protein Isoforms; D003300:Copper; D003907:Dexamethasone; D008668:Metallothionein; C109415:SOD1 G93A protein; D013482:Superoxide Dismutase; D010751:Phosphopyruvate Hydratase