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
Source: PubMed

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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Available from: Andres M Lozano, Aug 24, 2015
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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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    ABSTRACT: Oxidative stress is a common hallmark of neuronal cell death associated with neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, as well as brain stroke/ischemia and traumatic brain injury. Increased accumulation of reactive species of both oxygen (ROS) and nitrogen (RNS) has been implicated in mitochondrial dysfunction, energy impairment, alterations in metal homeostasis and accumulation of aggregated proteins observed in neurodegenerative disorders, which lead to the activation/modulation of cell death mechanisms that include apoptotic, necrotic and autophagic pathways. Thus, the design of novel antioxidant strategies to selectively target oxidative stress and redox imbalance might represent important therapeutic approaches against neurological disorders. This work reviews the evidence demonstrating the ability of genetically encoded antioxidant systems to selectively counteract neuronal cell loss in neurodegenerative diseases and ischemic brain damage. Because gene therapy approaches to treat inherited and acquired disorders offer many unique advantages over conventional therapeutic approaches, we discussed basic research/clinical evidence and the potential of virus-mediated gene delivery techniques for antioxidant gene therapy.
    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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    ABSTRACT: Our ageing society is confronted with a dramatic increase in incidence of age-related neurodegenerative diseases; biomedical research leading to novel therapeutic strategies is crucial to address this problem. Animal models of neurodegenerative conditions are invaluable in improving our understanding of the molecular basis of pathology, potentially revealing novel targets for intervention. Here, we review transgenic animal models of Alzheimer’s and Parkinson’s disease reported in mice, zebrafish, Caenorhabditis elegans and Drosophila melanogaster. This information will enable researchers to compare different animal models targeting disease-associated molecules by genomic engineering and to facilitate the development of novel animal models for any particular study, depending on the ultimate research goals.
    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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    ABSTRACT: Parkinson's disease (PD) is the second most common neurodegenerative disorder affecting approximately 1 % of the population older than 60 years. The administration of the proneurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in mice is the most widely used approach to elucidate the mechanisms of cell death involved in PD. However, the magnitude of the PD-like neurodegeneration induced by MPTP depends on many variables, including the regimen of its administration. It has been demonstrated that intranasal (i.n.) administration of MPTP constitutes a new route of toxin delivery to the brain that mimics environmental exposure to neurotoxins. Previous data showed that mice submitted to chronic and acute i.n. MPTP treatment displayed a robust (~80 %) and moderate (~55 %) loss of striatal dopamine, respectively. However, little is known about the neurodegenerative and neuroinflammatory processes following a subacute i.n. MPTP administration in mice. Here, the C57BL/6 mice were infused intranasally with MPTP (1 mg/nostril/day) during 4 consecutive days. At 7 and 28 days after the last administration, the subacute i.n. MPTP regime decreased the tyrosine hydroxylase (TH)-labeling in the striatum (40-50 %) and substantia nigra (25-30 %) and increased the astrogliosis in such brain areas at both time points. Taken together, our data showed that the subacute administration of MPTP into the nasal cavity of C57BL/6 mice induces long-lasting neurodegeneration and neuroinflammation in the nigrostriatal pathway, thus representing a valuable animal model for the investigation of neuroprotective strategies in PD.
    Neurotoxicity Research 05/2013; 25(1). DOI:10.1007/s12640-013-9401-8 · 3.15 Impact Factor
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