Metallothionein expression is altered in a transgenic murine model of familial amyotrophic lateral sclerosis.

Missense mutations in the gene encoding copper zinc superoxide dismutase (SOD1) have been found to cause one form of familial amyotrophic lateral sclerosis (FALS). Although the exact mechanism of disease is unknown, abnormalities in the ability of mutant SOD1 to bind zinc or copper ions may be crucial in the pathogenesis of disease. Because members of the metallothionein (MT) family of zinc and copper binding proteins function as important cellular regulators of metal ion bioavailability in the central nervous system, we used in situ hybridization and immunohistochemistry to study the expression pattern of these molecules in a transgenic mouse model of familial ALS. In adult wild-type mouse spinal cord, expression of MT-I and MT-II is restricted to ependymal cells and a subset of astrocytes located in white matter tracts, while MT-III synthesis is limited to neurons within gray matter. Compared to wild-type littermates, transgenic mice carrying the G93A SOD1 mutation demonstrate markedly increased expression of MT-I and MT-II within astrocytes in both white and gray matter as weakness develops. MT-III synthesis in neurons is also greatly upregulated as G93A SOD1 animals age, with glial cell expression of MT-III evident by later stages of the disease. Changes in MT expression occur before the onset of motor deficits or significant motor neuron pathology in G93A SOD1 mice and remarkably extend beyond ventral horn populations of neurons and glia. These results are consistent with the hypothesis that metallothioneins may serve an early and important protective function in FALS.

Gong YH ，Elliott JL 《EXPERIMENTAL NEUROLOGY》

Overexpression of metallothionein-I, a copper-regulating protein, attenuates intracellular copper dyshomeostasis and extends lifespan in a mouse model of amyotrophic lateral sclerosis caused by mutant superoxide dismutase-1.

Tokuda E ，Okawa E ，Watanabe S ，Ono S ... -  《-》

Disease progression in a transgenic model of familial amyotrophic lateral sclerosis is dependent on both neuronal and non-neuronal zinc binding proteins.

Puttaparthi K ，Gitomer WL ，Krishnan U ，Son M ，Rajendran B ，Elliott JL ... -  《-》

Human Cu/Zn superoxide dismutase (SOD1) overexpression in mice causes mitochondrial vacuolization, axonal degeneration, and premature motoneuron death and accelerates motoneuron disease in mice expressing a familial amyotrophic lateral sclerosis mutant SO

Cytosolic Cu/Zn superoxide dismutase (SOD1) is a ubiquitous small cytosolic metalloenzyme that catalyzes the conversion of superoxide anion to hydrogen peroxide (H(2)O(2)). Mutations in the SOD1 gene cause a familial form of amyotrophic lateral sclerosis (fALS). The mechanism by which mutant SOD1s causes ALS is not understood. Transgenic mice expressing multiple copies of fALS-mutant SOD1s develop an ALS-like motoneuron disease resembling ALS. Here we report that transgenic mice expressing a high concentration of wild-type human SOD1 (hSOD1(WT)) develop an array of neurodegenerative changes consisting of (1) swelling and vacuolization of mitochondria, predominantly in axons in the spinal cord, brain stem, and subiculum; (2) axonal degeneration in a number of long fiber tracts, predominantly the spinocerebellar tracts; and (3) at 2 years of age, a moderate loss of spinal motoneurons. Parallel to the development of neurodegenerative changes, hSOD1(WT) mice also develop mild motor abnormalities. Interestingly, mitochondrial vacuolization was associated with accumulation of hSOD1 immunoreactivity, suggesting that the development of mitochondrial pathology is associated with disturbed SOD1 turnover. In this study we also crossed hSOD1(WT) mice with a line of fALS-mutant SOD1 mice (hSOD1(G93A)) to generate "double" transgenic mice that express high levels of both wild-type and G93A mutant hSOD1. The "double" transgenic mice show accelerated motoneuron death, earlier onset of paresis, and earlier death as compared with hSOD1(G93A) littermates. Thus in vivo expression of high levels of wild-type hSOD1 is not only harmful to neurons in itself, but also increases or facilitates the deleterious action of a fALS-mutant SOD1. Our data indicate that it is important for motoneurons to control the SOD1 concentration throughout their processes, and that events that lead to improper synthesis, transport, or breakdown of SOD1 causing its accumulation are potentially dangerous.

Jaarsma D ，Haasdijk ED ，Grashorn JA ，Hawkins R ，van Duijn W ，Verspaget HW ，London J ，Holstege JC ... -  《NEUROBIOLOGY OF DISEASE》

Metallothionein proteins expression, copper and zinc concentrations, and lipid peroxidation level in a rodent model for amyotrophic lateral sclerosis.

Tokuda E ，Ono S ，Ishige K ，Naganuma A ，Ito Y ，Suzuki T ... -  《-》