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Metallothionein-mediated neuroprotection in genetically engineered mouse models of Parkinson's disease.
Brain Res Mol Brain Res. 2005 Mar 24; 134(1):67-75.BR

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 control(wt) (C57B1/6), metallothionein transgenic (MTtrans), metallothionein double gene knock (MTdko), alpha-synuclein knock out (alpha-syn(ko)), alpha-synuclein-metallothionein triple knock out (alpha-syn-MTtko), 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, TNFalpha, NFkappaB, 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. MTtrans and alpha-Syn(ko) mice were genetically resistant 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 control(wt) 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.

Authors+Show Affiliations

Department of Pharmacology, Physiology, and Therapeutics, University of North Dakota, 501 North Columbia Road, Grand Forks, ND 58203, USA. mebadi@medicine.nodak.eduNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.
Review

Language

eng

PubMed ID

15790531

Citation

Ebadi, Manuchair, et al. "Metallothionein-mediated Neuroprotection in Genetically Engineered Mouse Models of Parkinson's Disease." Brain Research. Molecular Brain Research, vol. 134, no. 1, 2005, pp. 67-75.
Ebadi M, Brown-Borg H, El Refaey H, et al. Metallothionein-mediated neuroprotection in genetically engineered mouse models of Parkinson's disease. Brain Res Mol Brain Res. 2005;134(1):67-75.
Ebadi, M., Brown-Borg, H., El Refaey, H., Singh, B. B., Garrett, S., Shavali, S., & Sharma, S. K. (2005). Metallothionein-mediated neuroprotection in genetically engineered mouse models of Parkinson's disease. Brain Research. Molecular Brain Research, 134(1), 67-75.
Ebadi M, et al. Metallothionein-mediated Neuroprotection in Genetically Engineered Mouse Models of Parkinson's Disease. Brain Res Mol Brain Res. 2005 Mar 24;134(1):67-75. PubMed PMID: 15790531.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR 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, PY - 2004/09/09/accepted PY - 2005/3/26/pubmed PY - 2005/6/14/medline PY - 2005/3/26/entrez SP - 67 EP - 75 JF - Brain research. Molecular brain research JO - Brain Res Mol Brain Res VL - 134 IS - 1 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 control(wt) (C57B1/6), metallothionein transgenic (MTtrans), metallothionein double gene knock (MTdko), alpha-synuclein knock out (alpha-syn(ko)), alpha-synuclein-metallothionein triple knock out (alpha-syn-MTtko), 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, TNFalpha, NFkappaB, 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. MTtrans and alpha-Syn(ko) mice were genetically resistant 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 control(wt) 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. SN - 0169-328X UR - https://www.unboundmedicine.com/medline/citation/15790531/Metallothionein_mediated_neuroprotection_in_genetically_engineered_mouse_models_of_Parkinson's_disease_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0169-328X(04)00450-4 DB - PRIME DP - Unbound Medicine ER -