Mutations of Human Cu, Zn Superoxide Dismutase Expressed in Transgenic Mice Cause Motor Neuron Disease

Abstract

ALS causes the degeneration of motor neurons in cortex, brainstem and spinal cord with consequent paralysis and death.¹ Most cases of ALS are sporadic and have an unknown etiology.² However, about 10–15% of all ALS cases are inherited. An adultonset, autosomal dominantly inherited trait is the predominant form³, although there is a rare, recessively inherited childhood-onset form of ALS in which survival can be quite long⁴. In 1991, a fraction of families with the familial form of ALS (FALS) showed linkage to a disease locus on human chromosome 21q.⁵ Shortly thereafter, in 1993, the target of mutation on chromosome 21q was shown to be the gene (SOD1) encoding Cu,Zn Superoxide dismutase (Cu,Zn SOD). At least 22 different missense mutations causing the substitution of one amino acid for another have now been found in FALS kindreds. Cu,Zn SOD is a metalloenzyme that catalyzes the dismutation of Superoxide (O₂×^-) to hydrogen peroxide (H₂O₂). The copper ion provides the redox center for the dismutation of Superoxide, while the zinc ion plays a structural role. Three different genes encoding Superoxide dismutases are present in the human genome. All three enzymes contain a transition metal in their active site, but differ in their subcellular localization. Only Cu,Zn SOD is mutated in FALS. Cu,Zn SOD is primarily cytosolic and is expressed in every cell within the body.^6,7 Why only motor neurons are affected by the mutations found in FALS is unknown. The mutations of Cu,Zn SOD found in affected families are primarily amino acid substitutions in structural regions of the polypeptide.8 No deletions of the human SOD1 gene have been described which suggests that expression of the mutant polypeptide is required for pathogenesis.