Metallothionein proteins expression, copper and zinc concentrations, and lipid peroxidation level in a rodent model for amyotrophic lateral sclerosis.
It has been hypothesized that copper-mediated oxidative stress contributes to the pathogenesis of familial amyotrophic lateral sclerosis (ALS), a fatal motor neuron disease in humans. To verify this hypothesis, we examined the copper and zinc concentrations and the amounts of lipid peroxides, together with that of the expression of metallothionein (MT) isoforms in a mouse model [superoxide dismutase1 transgenic (SOD1 Tg) mouse] of ALS. The expression of MT-I and MT-II (MT-I/II) isoforms were measured together with Western blotting, copper level, and lipid peroxides amounts increased in an age-dependent manner in the spinal cord, the region responsible for motor paralysis. A significant increase was already seen as early as 8-week-old SOD1 Tg mice, at which time the mice had not yet exhibited motor paralysis, and showed a further increase at 16 weeks of age, when paralysis was evident. Inversely, the spinal zinc level had significantly decreased at both 8 and 16 weeks of age. The third isoform, the MT-III level, remained at the same level as an 8-week-old wild-type mouse, finally increasing to a significant level at 16 weeks of age. It has been believed that a mutant SOD1 protein, encoded by a mutant SOD1, gains a novel cytotoxic function while maintaining its original enzymatic activity, and causes motor neuron death (gain-of-toxic function). Copper-mediated oxidative stress seems to be a probable underlying pathogenesis of gain-of-toxic function. Taking the above current concepts and the classic functions of MT into account, MTs could have a disease modifying property: the MT-I/II isoform for attenuating the gain-of-toxic function at the early stage of the disease, and the MT-III isoform at an advanced stage.
Tokuda
Eiichi
E
Laboratory of Clinical Pharmacy, College of Pharmacy, Nihon University, Chiba, Japan.
Ono
Shin-Ichi
S
Ishige
Kumiko
K
Naganuma
Akira
A
Ito
Yoshihisa
Y
Suzuki
Takashi
T
D000367:Age Factors; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D000818:Animals; D015153:Blotting, Western; D002531:Cerebellum / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D003300:Copper / Q000378:metabolism* / Q000494:pharmacology; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008054:Lipid Peroxides / Q000378:metabolism*; D008297:Male; D008668:Metallothionein / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D016133:Polymerase Chain Reaction; D020033:Protein Isoforms / Q000378:metabolism; D013116:Spinal Cord / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D015032:Zinc / Q000378:metabolism*
D008054:Lipid Peroxides; D020033:Protein Isoforms; D003300:Copper; D008668:Metallothionein; C109415:SOD1 G93A protein; D013482:Superoxide Dismutase; D015032:Zinc