c-Jun mediates axotomy-induced dopamine neuron death
            <i>in vivo</i>

Crocker, Stephen J.; Lamba, Wiplore R.; Smith, Patrice D.; Callaghan, Steve; Slack, Ruth S.; Anisman, Hymie; Park, David

doi:10.1073/pnas.231177098

Cited by 83 publications

(90 citation statements)

References 59 publications

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“…After being perfused transcardially, mouse brains were fixed in 4% paraformaldehyde and cryoprotected as described elsewhere (34). Midbrain sections containing the SNc (40 μm), pontine sections containing LC (40 μμ), and striatal (14 μm) sections were immunostained via avidin-biotin complex staining as described previously (26).…”

Section: Methodsmentioning

confidence: 99%

Progressive dopaminergic cell loss with unilateral-to-bilateral progression in a genetic model of Parkinson disease

Rousseaux

Marcogliese

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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DJ-1 mutations cause autosomal recessive early-onset Parkinson disease (PD). We report a model of PD pathology: the DJ1-C57 mouse. A subset of DJ-1–nullizygous mice, when fully backcrossed to a C57BL/6J background, display dramatic early-onset unilateral loss of dopaminergic (DA) neurons in their substantia nigra pars compacta , progressing to bilateral degeneration of the nigrostriatal axis with aging. In addition, these mice exhibit age-dependent bilateral degeneration at the locus ceruleus nucleus and display mild motor behavior deficits at aged time points. These findings effectively recapitulate the early stages of PD. Therefore, the DJ1-C57 mouse provides a tool to study the preclinical aspects of neurodegeneration. Importantly, by exome sequencing, we identify candidate modifying genes that segregate with the phenotype, providing potentially critical clues into how certain genes may influence the penetrance of DJ-1–related degeneration in mice.

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Section: Methodsmentioning

confidence: 99%

Progressive dopaminergic cell loss with unilateral-to-bilateral progression in a genetic model of Parkinson disease

Rousseaux

Marcogliese

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…For these experiments replication-deficient adenoviruses (Crocker et al, 2001) were used to infect a large fraction of neurons efficiently. Three different adenovirus constructs were made with CMV promoters driving the expression of enhanced green fluorescent protein (eGFP) alone (ad-GFP), Nrf2 and eGFP (ad-Nrf2), or Nrf2DN and eGFP (Ad-Nrf2DN).…”

Section: Overexpression Of Nrf2 Enhances Antioxidant Activity Of Neurmentioning

confidence: 99%

Coordinate Regulation of Glutathione Biosynthesis and Release by Nrf2-Expressing Glia Potently Protects Neurons from Oxidative Stress

Johnson²,

et al. 2003

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Astrocytes have a higher antioxidant potential in comparison to neurons. Pathways associated with this selective advantage include the transcriptional regulation of antioxidant enzymes via the action of the Cap'n'Collar transcription factor Nrf2 at the antioxidant response element (ARE). Here we show that Nrf2 overexpression can reengineer neurons to express this glial pathway and enhance antioxidant gene expression. However, Nrf2-mediated protection from oxidative stress is conferred primarily by glia in mixed cultures. The antioxidant properties of Nrf2-overexpressing glia are more pronounced than those of neurons, and a relatively small number of these glia (Ͻ 1% of total cell number added) could protect fully cocultured naive neurons from oxidative glutamate toxicity associated with glutathione (GSH) depletion. Microarray and biochemical analyses indicate a coordinated upregulation of enzymes involved in GSH biosynthesis (xCT cystine antiporter, ␥-glutamylcysteine synthetase, and GSH synthase), use (glutathione S-transferase and glutathione reductase), and export (multidrug resistance protein 1) with Nrf2 overexpression, leading to an increase in both media and intracellular GSH. Selective inhibition of glial GSH synthesis and the supplementation of media GSH indicated that an Nrf2-dependent increase in glial GSH synthesis was both necessary and sufficient for the protection of neurons, respectively. Neuroprotection was not limited to overexpression of Nrf2, because activation of endogenous glial Nrf2 by the small molecule ARE inducer, tert-butylhydroquinone, also protected against oxidative glutamate toxicity.

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“…Mice were challenged with MPTP once a day for five consecutive days (25 mg/kg, i.p., measured as free base; MPTP-HCl; SigmaAldrich) 1 week after adenovirus injection to permit sufficient time for retrograde transport and expression of the adenovirus-derived proteins (32,33). Mice used as controls received an equivalent volume of saline (0.9%) once daily.…”

Section: Mptp Administration In Vivomentioning

confidence: 99%

“…Brain tissues from mice injected with MPTP or saline were collected for immunohistochemical analyses as described previously (32,33). Antibodies used were TH (1:10,000; Immunostar), and immunoreactivity was visualized by using an avidin-biotin complex peroxidase reaction.…”

Section: Mptp Administration In Vivomentioning

confidence: 99%

Cytoplasmic Pink1 activity protects neurons from dopaminergic neurotoxin MPTP

Haque

Thomas

D'Souza

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

228

252

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PTEN-induced putative kinase 1 (Pink1) is a recently identified gene linked to a recessive form of familial Parkinson's disease (PD). The kinase contains a mitochondrial localization sequence and is reported to reside, at least in part, in mitochondria. However, neither the manner by which the loss of Pink1 contributes to dopamine neuron loss nor its impact on mitochondrial function and relevance to death is clear. Here, we report that depletion of Pink1 by RNAi increased neuronal toxicity induced by MPP ؉ . Moreover, wild-type Pink1, but not the G309D mutant linked to familial PD or an engineered kinase-dead mutant K219M, protects neurons against MPTP both in vitro and in vivo. Intriguingly, a mutant that contains a deletion of the putative mitochondrial-targeting motif was targeted to the cytoplasm but still provided protection against 1-methyl-4-phenylpyridine (MPP ؉ )/1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced toxicity. In addition, we also show that endogenous Pink1 is localized to cytosolic as well as mitochondrial fractions. Thus, our findings indicate that Pink1 plays a functional role in the survival of neurons and that cytoplasmic targets, in addition to its other actions in the mitochondria, may be important for this protective effect.Parkinson's disease ͉ neurodegeneration ͉ neuroprotection P arkinson's disease (PD) is a movement disorder with progressive loss of dopamine neurons in the substantia nigra pars compacta (SNc). The molecular events responsible for the loss of dopaminergic neurons in PD remain poorly understood. One common feature of PD is the dysfunction of mitochondria, which results in reduced complex I activity in the SNc (1, 2). Experimentally, inhibitors of complex I of the mitochondrial respiratory chain can recapitulate this selective dopaminergic neuronal loss and consequent behavioral deficits (1, 3-5). These observations support the hypothesis that nigral dopamine neurons are highly vulnerable to stress arising from mitochondrial dysfunction.Recently, several genes have been identified that cause PD (6). These genes include ␣-synuclein, parkin, PTEN-induced putative kinase 1 (Pink1), DJ-1, and LRRK2. Although several of the genes have been partially localized to the mitochondria, Pink1 is the only gene with a putative mitochondrial targeting motif. Several studies have shown that the mitochondrial targeting motif at the Nterminal region of Pink1 is sufficient to direct proteins to the mitochondria (7). Pink1 was initially identified as a PTEN-inducible transcript and contains a serine/threonine kinase domain (8). Interestingly, the G309D mutation of the kinase domain leads to a mild decrease in mitochondrial complex I activity, elevation of superoxide radicals, and increased lipid peroxidation (9). Studies with Drosophila lacking Pink1 showed mitochondrial pathology with the similar phenotype as seen in Parkin knockout flies (10, 11). The above observations suggest that mitochondrial dysfunction may be linked to the Pink1 PD phenotype.The mechanisms by which Pi...

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c-Jun mediates axotomy-induced dopamine neuron death in vivo

Cited by 83 publications

References 59 publications

Progressive dopaminergic cell loss with unilateral-to-bilateral progression in a genetic model of Parkinson disease

Progressive dopaminergic cell loss with unilateral-to-bilateral progression in a genetic model of Parkinson disease

Coordinate Regulation of Glutathione Biosynthesis and Release by Nrf2-Expressing Glia Potently Protects Neurons from Oxidative Stress

Cytoplasmic Pink1 activity protects neurons from dopaminergic neurotoxin MPTP

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