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Hypersensitivity of DJ-1-deficient mice to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and oxidative stress

Campbell Family Institute for Breast Cancer Research, Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada M5G 2C1.
Proceedings of the National Academy of Sciences (Impact Factor: 9.81). 05/2005; 102(14):5215-20. DOI: 10.1073/pnas.0501282102
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ABSTRACT Mutations of the DJ-1 (PARK7) gene are linked to familial Parkinson's disease. We used gene targeting to generate DJ-1-deficient mice that were viable, fertile, and showed no gross anatomical or neuronal abnormalities. Dopaminergic neuron numbers in the substantia nigra and fiber densities and dopamine levels in the striatum were normal. However, DJ-1-/- mice showed hypolocomotion when subjected to amphetamine challenge and increased striatal denervation and dopaminergic neuron loss induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrindine. DJ-1-/-embryonic cortical neurons showed increased sensitivity to oxidative, but not nonoxidative, insults. Restoration of DJ-1 expression to DJ-1-/- mice or cells via adenoviral vector delivery mitigated all phenotypes. WT mice that received adenoviral delivery of DJ-1 resisted 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrindine-induced striatal damage, and neurons overexpressing DJ-1 were protected from oxidative stress in vitro. Thus, DJ-1 protects against neuronal oxidative stress, and loss of DJ-1 may lead to Parkinson's disease by conferring hypersensitivity to dopaminergic insults.

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    • "It has been proposed that α-synuclein exerts protective effects (Hashimoto et al., 2002), while the A53P mutant α-synuclein sensitizes cells upon oxidative damage (Ko et al., 2000). DJ-1 oxidation induces its mitochondrial translocation (Canet-Aviles et al., 2004), and DJ-1 knockdown or mutants render cells more susceptible to parkinsonian toxins and oxidative stress (Taira et al., 2004; Kim et al., 2005). In addition, DJ-1 has been reported to regulate GSH levels (Liu et al., 2008). "
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    Pharmacology [?] Therapeutics 12/2013; 142(2). DOI:10.1016/j.pharmthera.2013.12.007 · 7.75 Impact Factor
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    • "Knockout mice lacking DJ-1, a redox-sensitive molecular chaperone protein, develop mild deficits in DA neurotransmission and mitochondrial dysfunction even in the absence of DA neuron loss (Chen et al. 2005; Goldberg et al. 2005; Kim et al. 2005). Knockdown of zebrafish DJ-1 using antisense MOs does not cause a decrease in DA neurons (Bretaud et al. 2007). "
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    Genes & genomics 08/2013; 35(4). DOI:10.1007/s13258-013-0116-2 · 0.57 Impact Factor
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    • "The MPTP administration in mice is the most widely used approach to investigate the mechanisms of cell death involved in PD (Bove and Perier 2012). The intravenous (i.v.), subcutaneous (s.c.), and intraperitoneal (i.p.) injections of MPTP lead to degeneration of mesencephalic DAergic neurons (Ballard et al. 1985; Kim et al. 2005; Smeyne and Jackson-Lewis 2005; Takahashi et al. 1997). More recently, it has been demonstrated that intranasal (i.n.) administration of MPTP also triggers neurodegeneration in the SN, providing evidences that nasal route may be used by environmental neurotoxins to reach the basal ganglia and develop parkinsonism (Aguiar Jr. et al. 2013; Prediger et al. 2006, 2010, 2012; Rojo et al. 2006). "
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