Shin-Ichi Ono,a,b Ei-Ichi Tokuda,a,c Eriko Okawa,a,d and Shunsuke Watanabea,e aLaboratory of Clinical Medicine, School of Pharmacy, Nihon University, Funabashi, Chiba 274-8555, Japan bDivision of Neurology, Akiru Municipal Medical Center, Tokyo 197-0834, Japan cDepartment of Medical Biosciences, Clinical Chemistry, Umeå University, Umeå, Sweden dDepartment of Pharmacy, St. Marianna University School of Medicine Hospital, Kawasaki, Kanagawa, 216-8511, Japan eDepartment of Pharmacy, International University of Health and Welfare, Atami Hospital, Atami, Shizuoka, 413-0012, Japan
Mutation in superoxide diamutase1 (SOD1) is a cause of hereditary form of amyotrophic lateral sclerosis (ALS). Novel acquired toxicity (gain-of-function) is believed to play a crucial role. We propose that
the nature of mutant SOD1 toxicity is disruption of intracellular Cu homeostasis. We provide evidences that copper transporters and chaperons are geared to accumulate Cu ion in the cells, and its excretion is downregulated with mutant SOD1 (“intracellular copper dysregulation” theory). Intracellular Cu modification using a Cu chelator and/or metallothionein resulted in a favorable outcome in an experimental study with a rodent model for hereditary form of ALS.