Preferential vulnerability of mesencephalic dopamine neurons to glutamate transporter dysfunction

Nafia, Imane; Ré, Diane B.; Masmejean, F.; Melon, Christophe; Kachidian, Philippe; Goff, L. Kerkerian‐Le; Nieoullon, A.; Had‐Aissouni, Laurence

doi:10.1111/j.1471-4159.2007.05146.x

Cited by 38 publications

(32 citation statements)

References 73 publications

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“…EAAC1 −/− mice have reduced neuronal glutathione content due to the lack of EAAC1-mediated neuronal cysteine uptake. 9,13,33,34 To assess the level of oxidative stress in EAAC1 −/− midbrain dopaminergic neurons, brain sections were immuno-stained for the presence of nTyr-modified proteins. 35 SNc dopaminergic neurons in the EAAC1 −/− mice showed an increase in nTyr immunoreactivity (Fig 3A, B).…”

Section: Resultsmentioning

confidence: 99%

“…EAAC1 was diffusely distributed in the midbrain, consistent with its ubiquitous expression over neuronal cell bodies and processes.10,11 However, there was higher EAAC1 expression over dopaminergic (TH-positive) neurons (Fig 4A), in agreement with previous reports. 11,33 Human postmortem midbrain sections were similarly stained for EAAC1 and TH, but for technical reasons the anti-NeuN antibody could not be used with the postmortem tissue. As in the mouse brain, normal human brain showed increased EAAC1 expression in dopaminergic (TH-positive) neurons (see Fig 4B).…”

Section: Resultsmentioning

confidence: 99%

“…8,38 Consistent with this idea, pharmacological inhibition of EAAC1 has been reported to produce glutathione loss and subsequent cell death selectively in the dopaminergic neurons of rat and mouse midbrain. 33 Similarly, a transgenic mouse constructed by Chinta and colleagues, 39 in which glutathione synthesis is impaired in catecholaminergic neurons, exhibits increased protein nitrosylation, reduced mitochondrial complex 1 activity, and a modest degree of dopaminergic cell loss. Together, these findings suggest a key role for EAAC1 in dopaminergic neuronal glutathione metabolism and a contributory role for glutathione depletion in dopaminergic neuronal death.…”

Section: Discussionmentioning

confidence: 99%

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N‐acetylcysteine prevents loss of dopaminergic neurons in the EAAC1^−/− mouse

Berman

Chan

Brennan

et al. 2010

Annals of Neurology

123

107

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Objective Dopaminergic neuronal death in Parkinson’s disease (PD) is accompanied by oxidative stress and preceded by glutathione depletion. The development of disease-modifying therapies for PD has been hindered by a paucity of animal models that mimic these features and demonstrate an age-related progression. The EAAC1−/− mouse may be useful in this regard, because EAAC1−/− mouse neurons have impaired neuronal cysteine uptake, resulting in reduced neuronal glutathione content and chronic oxidative stress. Here we aimed to (1) characterize the age-related changes in nigral dopaminergic neurons in the EAAC1−/− mouse, and (2) use the EAAC1−/− mouse to evaluate N-acetylcysteine, a membrane-permeable cysteine pro-drug, as a potential disease-modifying intervention for PD. Methods Wild-type mice, EAAC1−/− mice, and EAAC1−/− mice chronically treated with N-acetylcysteine were evaluated at serial time points for evidence of oxidative stress, dopaminergic cell death, and motor abnormalities. Results EAAC1−/− mice showed age-dependent loss of dopaminergic neurons in the substantia nigra pars compacta, with more than 40% of these neurons lost by age 12 months. This neuronal loss was accompanied by increased nitrotyrosine formation, nitrosylated α-synuclein, and microglial activation. These changes were substantially reduced in mice that received N-acetylcysteine. Interpretation These findings suggest that the EAAC1−/− mouse may be a useful model of the chronic neuronal oxidative stress that occurs in PD. The salutary effects of N-acetylcysteine in this mouse model provide an impetus for clinical evaluation of glutathione repletion in PD.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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N‐acetylcysteine prevents loss of dopaminergic neurons in the EAAC1^−/− mouse

Berman

Chan

Brennan

et al. 2010

Annals of Neurology

123

107

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“…Protein extracts from rat striatum were used as a positive control, since the specificity of the antibodies has already been verified in this species (Bender et al, 2001; Kawaguchi and Hirano, 2002; Meier and Grantyn, 2004; Nafia et al, 2008; Rostkowski et al, 2009). Western-blot experiments showed that the antibodies produced bands that were located at the same level in the gel for both rat striatum and tree shrew brain protein extracts.…”

Section: Resultsmentioning

confidence: 99%

Neurochemical Characterization of the Tree Shrew Dorsal Striatum

Rice¹,

Roberts²,

Meléndez-Ferro³

et al. 2011

Front. Neuroanat.

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The striatum is a major component of the basal ganglia and is associated with motor and cognitive functions. Striatal pathologies have been linked to several disorders, including Huntington’s, Tourette’s syndrome, obsessive–compulsive disorders, and schizophrenia. For the study of these striatal pathologies different animal models have been used, including rodents and non-human primates. Rodents lack on morphological complexity (for example, the lack of well defined caudate and putamen nuclei), which makes it difficult to translate data to the human paradigm. Primates, and especially higher primates, are the closest model to humans, but there are ever-increasing restrictions to the use of these animals for research. In our search for a non-primate animal model with a striatum that anatomically (and perhaps functionally) can resemble that of humans, we turned our attention to the tree shrew. Evolutionary genetic studies have provided strong data supporting that the tree shrews (Scadentia) are one of the closest groups to primates, although their brain anatomy has only been studied in detail for specific brain areas. Morphologically, the tree shrew striatum resembles the primate striatum with the presence of an internal capsule separating the caudate and putamen, but little is known about its neurochemical composition. Here we analyzed the expression of calcium-binding proteins, the presence and distribution of the striosome and matrix compartments (by the use of calbindin, tyrosine hydroxylase, and acetylcholinesterase immunohistochemistry), and the GABAergic system by immunohistochemistry against glutamic acid decarboxylase and Golgi impregnation. In summary, our results show that when compared to primates, the tree shrew dorsal striatum presents striking similarities in the distribution of most of the markers studied, while presenting some marked divergences when compared to the rodent striatum.

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“…A deficiency of EAATs has been associated with reduced glutathione (GSH) levels and increased oxidant levels, as well as neurodegeneration in the hippocampus at an advanced age [12]. EAAT dysfunction can trigger GSH depletion, which ensures astrocyte oxidative death and mesencephalic dopamine neuron vulnerability [13,14]. GSH depletion is suggested to be a primary event in the pathogenesis of PD [15].…”

Section: Genomic Factors Associated With Thiamine In Parkinson's Diseasementioning

confidence: 99%