Document Information

PMID 14625013  (  )
Title Zinc amplifies mSOD1-mediated toxicity in a transgenic mouse model of amyotrophic lateral sclerosis.
Abstract Transgenic mice overexpressing the human mutated form (G93A) of Cu,Zn-superoxide dismutase (mSOD1) develop motor neuron degeneration resembling amyotrophic lateral sclerosis. In vitro studies have shown that mSOD1-induced, reactive oxygen species-mediated apoptosis of motor neurons depends on the presence of copper and the relative absence of zinc. Oral intake of zinc sulphate induces the expression of metallothioneins, enzymes that decrease oxidative stress, and leads to higher serum zinc, and lower copper levels. We therefore tested the effect of chronic oral administration of zinc sulfate (0.075 and 0.375 g/kg) on disease onset and survival of mSOD1 transgenic mice. We observed that zinc sulfate, rather than prolonging survival, decreased survival. We conclude that zinc sulfate amplifies the mSOD1 transgenic mouse phenotype. This finding may shed more light on the role of zinc in mSOD1-mediated toxicity. Neurosurgery, G.03.228, University Medical Center Utrecht, P.O. Box 85500, 3508 GA, Utrecht, The Netherlands.

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Targets by SciMiner Summary

HUGO ID Symbol Target Name #Occur ActualStr
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))30SOD1 | mSOD1 | superoxide dismutase |

 

Targets by SciMiner Full list

HUGO ID Symbol Name ActualStr Score FlankingText
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))mSOD11.4human mutated form (G93A) G93A of Cu Zn-superoxide dismutase (mSOD1) mSOD1 develop motor neuron degeneration resembling amyotrophic lateral sclerosis
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))mSOD11.40.375 g/kg) g kg on disease onset and survival of mSOD1 transgenic mice
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))mSOD11.4We conclude that zinc sulfate amplifies the mSOD1 transgenic mouse phenotype
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))SOD11.4but mutations in the gene encoding Cu Zn-superoxide dismutase (SOD1) SOD1 are found in approximately 2% of ALS patients 12
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))SOD11.4Transgenic mice overexpressing human SOD1 carrying the G93A mutation (mSOD1) mSOD1 develop a rapidly progressive
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))mSOD11.4Transgenic mice overexpressing human SOD1 carrying the G93A mutation (mSOD1) mSOD1 develop a rapidly progressive muscular weakness due to motor neuron
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))SOD11.4SOD1 is a metalloenzyme that catalyzes the conversion of superoxide to
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))mSOD11.4Such gained properties of mSOD1 include increased formation of free radicals with hydrogen peroxide as
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))SOD11.4In vitro studies showed that mutations in SOD1 destabilize the protein and decrease the affinity of SOD1 for
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))SOD11.4in SOD1 destabilize the protein and decrease the affinity of SOD1 for zinc up to 50-fold compared to the wild type
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))SOD11.4Zinc-deficient SOD1 leads to an increase in nitrotyrosine formation and induces apoptosis
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))SOD11.4This toxicity required copper to be bound to SOD1 and was not present when SOD1 was replete with zinc
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))SOD11.4to be bound to SOD1 and was not present when SOD1 was replete with zinc 3
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))mSOD11.4upregulation of MT's is seen in the spinal cord of mSOD1 transgenic mice 11 and reduction of MT-I and -II significantly
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))mSOD11.4and reduction of MT-I and -II significantly reduces survival of mSOD1 transgenic mice 10
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))SOD11.4expression of MT's would be neuroprotective in transgenic high-copy human SOD1 G93A mice (Jackson Jackson Laboratory Bar Harbor MN
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))SOD11.4G93A male SOD1 mice were crossbred with non-transgenic Balb/C Balb C females
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))SOD11.4Prior to the G93A SOD1 experiment the effect of high dose zinc sulphate on hematological
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))SOD11.4In the G93A SOD1 mice the hind-paw extension reflex test was performed 5 days
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))mSOD11.4In untreated mSOD1 transgenic mice a similar though clearly more intense staining pattern
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))mSOD11.4in immunoreactivity for MT's were observed between zinc-treated and untreated mSOD1 transgenic mice ( Figs 2B C
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))mSOD11.4would attenuate motor neuron death and thus extend survival of mSOD1 transgenic mice
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))mSOD11.4zinc sulphate (0.375 0.375 g/kg) g kg decreased survival of mSOD1 transgenic mice
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))mSOD11.4level in the spinal cord of both treated and untreated mSOD1 transgenic mice but a further upregulation of MT in the
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))mSOD11.4The selective toxicity in mSOD1 transgenic mice may be due to enhanced motor neuron death
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))mSOD11.4raises two related questions why is zinc not neuroprotective in mSOD1 transgenic mice and why does it even appear to accelerate
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))mSOD11.4maximum in the spinal cord (and and intestinal wall of mSOD1 transgenic mice 11 so that a further upregulation cannot be
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))mSOD11.4direct toxic effect of zinc on motor neurons 18 of mSOD1 transgenic mice
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))superoxide dismutase1.0transgenic mice overexpressing the human mutated form g93a of cu zn superoxide dismutase msod1 develop motor neuron degeneration resembling amyotrophic lateral sclerosis.
11179SOD1superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))superoxide dismutase1.0the exact etiology of the disease is unknown but mutations in the gene encoding cu zn superoxide dismutase sod1 are found in approximately 2% of als patients [ 12 ].