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

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.

SUBMITTER: Kim RH

PROVIDER: S-EPMC555037 | biostudies-literature |

REPOSITORIES: biostudies-literature

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SIRT2 enhances 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced nigrostriatal damage via apoptotic pathway.

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Project description:Acute intoxication with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induces nigrostriatal neurodegeneration that reflects Parkinson's disease (PD) pathobiology. The model is commonly used for rodent studies of PD pathogenesis and diagnostics and for developmental therapeutics. However, tests of motor function in MPTP-intoxicated mice have yielded mixed results. This unmet need reflects, in part, lesion severity, animal variability, and the overall test sensitivity and specificity. In attempts to standardize rodent motor function and behavioral tests, mice were trained on the rotarod or habituated in an open field test chamber, and baseline performance measurements were collected prior to MPTP intoxication. One week following MPTP intoxication, motor function and behavior were assessed and baseline measurements applied to post-MPTP measurements with normalization to PBS controls. Rotarod and open field tests assessed in this manner demonstrated significant differences between MPTP- and saline-treated mice, while tests of neuromuscular strength and endurance did not. We conclude that the rotarod and open field tests provide reliable measures of motor function for MPTP-intoxicated mice.

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2006-05-12 | GSE4788 | GEO

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Rho kinase II interference by small hairpin RNA ameliorates 1?methyl?4?phenyl?1,2,3,6?tetrahydropyridine?induced parkinsonism in mice.

Project description:Novel therapeutic targets are required for the treatment of Parkinson's disease (PD). Previous studies suggest that the Rho/Rho?associated, coiled?coil?containing protein kinases (ROCKs) signaling pathway may be a promising therapeutic target in PD. To elucidate the importance of ROCKII in the pathogenesis of dopaminergic (DA) neuron loss and to investigate the efficacy of ROCK inhibitors in PD, ROCKII expression in the substantia nigra (SN) of mice was silenced through the injection of a lentivirus?based small hairpin RNA system. Empty lentivirus vectors served as controls. Mice were subsequently challenged with 1?methyl?4?phenyl?1,2,3,6?tetrahydropyridine (MPTP). The expression levels and activity of ROCKII were elevated in tyrosine hydroxylase?positive neurons and in cluster of differentiation (CD) 11b?positive microglia within the SN of MPTP?treated mice, which was accompanied by an increased level of expression of inducible nitric oxide synthase (iNOS) and activation of the Toll?like receptor (TLR)2/nuclear factor (NF)??B signaling pathway in M1 microglia. ROCKII interference (RI) significantly improved movement disorder and attenuated DA neuron loss induced by MPTP. In addition, RI inhibited the activation of M1 microglia in the SN, exhibiting reduced activity of the TLR2/NF??B signaling pathway and decreased expression levels of iNOS and inflammatory factors, including interleukin (IL)?1? and IL?6. The results of the present study verify that ROCKII participates in the loss of DA neurons induced by MPTP and suggest that ROCKII inhibition may be a promising therapeutic target for PD.

| S-EPMC5355756 | biostudies-literature

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