Metallothionein-mediated neuroprotection in genetically engineered mouse models of Parkinson's disease

Manuchair Ebadi, Holly Brown-Borg, Hesham El Refaey, Brij B Singh, Scott Garrett, Shaik Shavali, Sushil K. Sharma

Research output: Contribution to journalReview article

84 Citations (Scopus)

Abstract

Parkinson's disease is characterized by a progressive loss of dopaminergic neurons in the substantia nigra zona compacta, and in other sub-cortical nuclei associated with a widespread occurrence of Lewy bodies. The cause of cell death in Parkinson's disease is still poorly understood, but a defect in mitochondrial oxidative phosphorylation and enhanced oxidative and nitrative stresses have been proposed. We have studied controlwt (C57B1/6), metallothionein transgenic (MTtrans), metallothionein double gene knock (MT dko), α-synuclein knock out (α-synko), α-synuclein-metallothionein triple knock out (α-syn-MT tko), weaver mutant (wv/wv) mice, and Ames dwarf mice to examine the role of peroxynitrite in the etiopathogenesis of Parkinson's disease and aging. Although MTdko mice were genetically susceptible to 1, methyl, 4-phenyl, 1,2,3,6-tetrahydropyridine (MPTP) Parkinsonism, they did not exhibit any overt clinical symptoms of neurodegeneration and gross neuropathological changes as observed in wv/wv mice. Progressive neurodegenerative changes were associated with typical Parkinsonism in wv/wv mice. Neurodegenerative changes in wv/wv mice were observed primarily in the striatum, hippocampus and cerebellum. Various hallmarks of apoptosis including caspase-3, TNFα, NFκB, metallothioneins (MT-1, 2) and complex-1 nitration were increased; whereas glutathione, complex-1, ATP, and Ser(40)-phosphorylation of tyrosine hydroxylase, and striatal 18F-DOPA uptake were reduced in wv/wv mice as compared to other experimental genotypes. Striatal neurons of wv/wv mice exhibited age-dependent increase in dense cored intra-neuronal inclusions, cellular aggregation, proto-oncogenes (c-fos, c-jun, caspase-3, and GAPDH) induction, inter-nucleosomal DNA fragmentation, and neuro-apoptosis. MT trans and α-Synko mice were geneticallyresistant to MPTP-Parkinsonism and Ames dwarf mice possessed significantly higher concentrations of striatal coenzyme Q10 and metallothioneins (MT 1, 2) and lived almost 2.5 times longer as compared to controlwt mice. A potent peroxynitrite ion generator, 3-morpholinosydnonimine (SIN-1)-induced apoptosis was significantly attenuated in MTtrans fetal stem cells. These data are interpreted to suggest that peroxynitrite ions are involved in the etiopathogenesis of Parkinson's disease, and metallothionein-mediated coenzyme Q10 synthesis may provide neuroprotection.

Original languageEnglish (US)
Pages (from-to)67-75
Number of pages9
JournalMolecular Brain Research
Volume134
Issue number1
DOIs
StatePublished - Mar 24 2005
Externally publishedYes

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Metallothionein
Parkinson Disease
coenzyme Q10
Corpus Striatum
Peroxynitrous Acid
Parkinsonian Disorders
Synucleins
Apoptosis
Caspase 3
Neuroprotection
Fetal Stem Cells
Ions
fos Genes
Lewy Bodies
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
Dopaminergic Neurons
Inclusion Bodies
Oxidative Phosphorylation
Herpes Zoster
Tyrosine 3-Monooxygenase

Keywords

  • 18F-DOPA
  • a-synuclein knockout mice
  • Ames dwarf mice
  • Fetal stem cell transplantation
  • Homozygous weaver mutant mice (WMhomo)
  • Metallothionein double gene knockout mice
  • Metallothionein transgenic mice
  • MicroPET imaging
  • Parkinson's disease

ASJC Scopus subject areas

  • Molecular Biology
  • Cellular and Molecular Neuroscience

Cite this

Metallothionein-mediated neuroprotection in genetically engineered mouse models of Parkinson's disease. / Ebadi, Manuchair; Brown-Borg, Holly; El Refaey, Hesham; Singh, Brij B; Garrett, Scott; Shavali, Shaik; Sharma, Sushil K.

In: Molecular Brain Research, Vol. 134, No. 1, 24.03.2005, p. 67-75.

Research output: Contribution to journalReview article

Ebadi, Manuchair ; Brown-Borg, Holly ; El Refaey, Hesham ; Singh, Brij B ; Garrett, Scott ; Shavali, Shaik ; Sharma, Sushil K. / Metallothionein-mediated neuroprotection in genetically engineered mouse models of Parkinson's disease. In: Molecular Brain Research. 2005 ; Vol. 134, No. 1. pp. 67-75.
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T1 - Metallothionein-mediated neuroprotection in genetically engineered mouse models of Parkinson's disease

AU - Ebadi, Manuchair

AU - Brown-Borg, Holly

AU - El Refaey, Hesham

AU - Singh, Brij B

AU - Garrett, Scott

AU - Shavali, Shaik

AU - Sharma, Sushil K.

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N2 - Parkinson's disease is characterized by a progressive loss of dopaminergic neurons in the substantia nigra zona compacta, and in other sub-cortical nuclei associated with a widespread occurrence of Lewy bodies. The cause of cell death in Parkinson's disease is still poorly understood, but a defect in mitochondrial oxidative phosphorylation and enhanced oxidative and nitrative stresses have been proposed. We have studied controlwt (C57B1/6), metallothionein transgenic (MTtrans), metallothionein double gene knock (MT dko), α-synuclein knock out (α-synko), α-synuclein-metallothionein triple knock out (α-syn-MT tko), weaver mutant (wv/wv) mice, and Ames dwarf mice to examine the role of peroxynitrite in the etiopathogenesis of Parkinson's disease and aging. Although MTdko mice were genetically susceptible to 1, methyl, 4-phenyl, 1,2,3,6-tetrahydropyridine (MPTP) Parkinsonism, they did not exhibit any overt clinical symptoms of neurodegeneration and gross neuropathological changes as observed in wv/wv mice. Progressive neurodegenerative changes were associated with typical Parkinsonism in wv/wv mice. Neurodegenerative changes in wv/wv mice were observed primarily in the striatum, hippocampus and cerebellum. Various hallmarks of apoptosis including caspase-3, TNFα, NFκB, metallothioneins (MT-1, 2) and complex-1 nitration were increased; whereas glutathione, complex-1, ATP, and Ser(40)-phosphorylation of tyrosine hydroxylase, and striatal 18F-DOPA uptake were reduced in wv/wv mice as compared to other experimental genotypes. Striatal neurons of wv/wv mice exhibited age-dependent increase in dense cored intra-neuronal inclusions, cellular aggregation, proto-oncogenes (c-fos, c-jun, caspase-3, and GAPDH) induction, inter-nucleosomal DNA fragmentation, and neuro-apoptosis. MT trans and α-Synko mice were geneticallyresistant to MPTP-Parkinsonism and Ames dwarf mice possessed significantly higher concentrations of striatal coenzyme Q10 and metallothioneins (MT 1, 2) and lived almost 2.5 times longer as compared to controlwt mice. A potent peroxynitrite ion generator, 3-morpholinosydnonimine (SIN-1)-induced apoptosis was significantly attenuated in MTtrans fetal stem cells. These data are interpreted to suggest that peroxynitrite ions are involved in the etiopathogenesis of Parkinson's disease, and metallothionein-mediated coenzyme Q10 synthesis may provide neuroprotection.

AB - Parkinson's disease is characterized by a progressive loss of dopaminergic neurons in the substantia nigra zona compacta, and in other sub-cortical nuclei associated with a widespread occurrence of Lewy bodies. The cause of cell death in Parkinson's disease is still poorly understood, but a defect in mitochondrial oxidative phosphorylation and enhanced oxidative and nitrative stresses have been proposed. We have studied controlwt (C57B1/6), metallothionein transgenic (MTtrans), metallothionein double gene knock (MT dko), α-synuclein knock out (α-synko), α-synuclein-metallothionein triple knock out (α-syn-MT tko), weaver mutant (wv/wv) mice, and Ames dwarf mice to examine the role of peroxynitrite in the etiopathogenesis of Parkinson's disease and aging. Although MTdko mice were genetically susceptible to 1, methyl, 4-phenyl, 1,2,3,6-tetrahydropyridine (MPTP) Parkinsonism, they did not exhibit any overt clinical symptoms of neurodegeneration and gross neuropathological changes as observed in wv/wv mice. Progressive neurodegenerative changes were associated with typical Parkinsonism in wv/wv mice. Neurodegenerative changes in wv/wv mice were observed primarily in the striatum, hippocampus and cerebellum. Various hallmarks of apoptosis including caspase-3, TNFα, NFκB, metallothioneins (MT-1, 2) and complex-1 nitration were increased; whereas glutathione, complex-1, ATP, and Ser(40)-phosphorylation of tyrosine hydroxylase, and striatal 18F-DOPA uptake were reduced in wv/wv mice as compared to other experimental genotypes. Striatal neurons of wv/wv mice exhibited age-dependent increase in dense cored intra-neuronal inclusions, cellular aggregation, proto-oncogenes (c-fos, c-jun, caspase-3, and GAPDH) induction, inter-nucleosomal DNA fragmentation, and neuro-apoptosis. MT trans and α-Synko mice were geneticallyresistant to MPTP-Parkinsonism and Ames dwarf mice possessed significantly higher concentrations of striatal coenzyme Q10 and metallothioneins (MT 1, 2) and lived almost 2.5 times longer as compared to controlwt mice. A potent peroxynitrite ion generator, 3-morpholinosydnonimine (SIN-1)-induced apoptosis was significantly attenuated in MTtrans fetal stem cells. These data are interpreted to suggest that peroxynitrite ions are involved in the etiopathogenesis of Parkinson's disease, and metallothionein-mediated coenzyme Q10 synthesis may provide neuroprotection.

KW - 18F-DOPA

KW - a-synuclein knockout mice

KW - Ames dwarf mice

KW - Fetal stem cell transplantation

KW - Homozygous weaver mutant mice (WMhomo)

KW - Metallothionein double gene knockout mice

KW - Metallothionein transgenic mice

KW - MicroPET imaging

KW - Parkinson's disease

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