Disease progression in a transgenic model of familial amyotrophic lateral sclerosis is dependent on both neuronal and non-neuronal zinc binding proteins.
Mutations in the Cu/Zn superoxide dismutase (SOD1) gene cause one form of familial amyotrophic lateral sclerosis, a progressive disorder of motor neurons leading to weakness and death of affected individuals. Experiments using both transgenic mice expressing mutant SOD1 and SOD1 knock-out mice have demonstrated that disease is caused by a toxic gain of function and not by a loss of normal SOD1 activity. Precise mechanisms underlying mutant SOD1 toxicity are unclear but may involve abnormal interactions between zinc and SOD1. The metallothioneins (MTs) represent a family of zinc binding proteins that can function as zinc chaperones for apo-SOD1 in vitro. We hypothesized that manipulation of metallothioneins in vivo might alter the disease phenotype of transgenic mice expressing G93A SOD1 and therefore crossed this line with MT-I and MT-II or MT-III knock-out mice. G93A SOD1 mice deficient of either MT-I and MT-II or MT-III exhibited significant reductions in survival compared with G93A SOD1 mice. In addition, motor dysfunction was markedly accelerated in G93A SOD1 mice deficient in metallothioneins with regard to onset (MT-I and MT-II) or progression (MT-III). These results indicate that the disease course in G93A SOD1 mice is dependent on levels of metallothionein expression. Because MT-I and MT-II are expressed in glia whereas MT-III is found in neurons, these results also indicate that primary changes within non-neuronal cells can affect mutant SOD1-induced disease and do so in ways distinct from primary neuronal changes.
Puttaparthi
Krishna
K
Department of Neurology, University of Texas, Southwestern Medical Center, Dallas, Texas 75390, USA.
Gitomer
William L
WL
Krishnan
Uma
U
Son
Marjatta
M
Rajendran
Bhagya
B
Elliott
Jeffrey L
JL
D000690:Amyotrophic Lateral Sclerosis / Q000473:pathology / Q000503:physiopathology*; D000818:Animals; D015153:Blotting, Western; D002452:Cell Count; D003433:Crosses, Genetic; D004195:Disease Models, Animal; D018450:Disease Progression; D005904:Glial Fibrillary Acidic Protein / Q000096:biosynthesis; D006801:Humans; D008668:Metallothionein / Q000172:deficiency* / Q000235:genetics; D000090023:Metallothionein 3; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000172:deficiency* / Q000235:genetics; D009457:Neuroglia / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D013116:Spinal Cord / Q000473:pathology; D013482:Superoxide Dismutase / Q000096:biosynthesis / Q000235:genetics; D016019:Survival Analysis; D015032:Zinc / Q000378:metabolism*
D005904:Glial Fibrillary Acidic Protein; D000090023:Metallothionein 3; D009419:Nerve Tissue Proteins; D008668:Metallothionein; C109415:SOD1 G93A protein; D013482:Superoxide Dismutase; D015032:Zinc