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See detailProbenecid potentiates MPTP/MPP+ toxicity by interference with cellular energy metabolism.
Alvarez-Fischer, Daniel; Noelker, Carmen; Grünewald, Anne UL et al

in Journal of neurochemistry (2013), 127(6), 782-92

The uricosuric agent probenecid is co-administered with the dopaminergic neurotoxin MPTP to produce a chronic mouse model of Parkinson's disease. It has been proposed that probenecid serves to elevate ... [more ▼]

The uricosuric agent probenecid is co-administered with the dopaminergic neurotoxin MPTP to produce a chronic mouse model of Parkinson's disease. It has been proposed that probenecid serves to elevate concentrations of MPTP in the brain by reducing renal elimination of the toxin. However, this mechanism has never been formally demonstrated to date and is questioned by our previous data showing that intracerebral concentrations of MPP(+), the active metabolite of MPTP, are not modified by co-injection of probenecid. In this study, we investigated the potentiating effects of probenecid in vivo and in vitro arguing against the possibility of altered metabolism or impaired renal elimination of MPTP. We find that probenecid (i) is toxic in itself to several neuronal populations apart from dopaminergic neurons, and (ii) that it also potentiates the effects of other mitochondrial complex I inhibitors such as rotenone. On a mechanistic level, we show that probenecid is able to lower intracellular ATP concentrations and that its toxic action on neuronal cells can be reversed by extracellular ATP. Probenecid can potentiate the effect of mitochondrial toxins due to its impact on ATP metabolism and could therefore be useful to model atypical parkinsonian syndromes. [less ▲]

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See detailThe E3-ubiquitin ligase TRIM2 regulates neuronal polarization.
Khazaei, Mohammad R.; Bunk, Eva C.; Hillje, Anna-Lena et al

in Journal of Neurochemistry (2011), 117(1), 29-37

The establishment of a polarized morphology with a single axon and multiple dendrites is an essential step during neuronal differentiation. This cellular polarization is largely depending on changes in ... [more ▼]

The establishment of a polarized morphology with a single axon and multiple dendrites is an essential step during neuronal differentiation. This cellular polarization is largely depending on changes in the dynamics of the neuronal cytoskeleton. Here, we show that the tripartite motif (TRIM)-NHL protein TRIM2 is regulating axon specification in cultured mouse hippocampal neurons, where one of several initially indistinguishable neurites is selected to become the axon. Suppression of TRIM2 by RNA interference results in the loss of neuronal polarity while over-expression of TRIM2 induces the specification of multiple axons. TRIM2 conducts its function during neuronal polarization by ubiquitination of the neurofilament light chain. Together, our results imply an important function of TRIM2 for axon outgrowth during development. [less ▲]

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See detailMicroglial activation depends on beta-amyloid conformation: role of the formylpeptide receptor 2
Heurtaux, Tony UL; Michelucci, Alessandro UL; Losciuto, Sophie UL et al

in Journal of Neurochemistry (2010), 114(2), 576-586

Alzheimer's disease (AD) is characterized by the presence of extracellular deposits referred to beta-amyloid (Abeta) complexes or senile plaques. Abeta peptide is firstly produced as monomers, readily ... [more ▼]

Alzheimer's disease (AD) is characterized by the presence of extracellular deposits referred to beta-amyloid (Abeta) complexes or senile plaques. Abeta peptide is firstly produced as monomers, readily aggregating to form multimeric complexes, of which the smallest aggregates are known to be the most neurotoxic. In AD patients, abundant reactive microglia migrate to and surround the Abeta plaques. Though it is well known that microglia are activated by Abeta, little is known about the peptide conformation and the signaling cascades responsible for this activation. In this study, we have stimulated murine microglia with different Abeta(1-42) forms, inducing an inflammatory state, which was peptide conformation-dependent. The lightest oligomeric forms induced a more violent inflammatory response, whereas the heaviest oligomers and the fibrillar conformation were less potent inducers. BocMLF, a formylpeptide chemotactic receptor 2 antagonist, decreased the oligomeric Abeta-induced inflammatory response. The Abeta-induced signal transduction was found to depend on phosphorylation mechanisms mediated by MAPKs and on activator protein 1/nuclear factor kappa-light-chain-enhancer of activated B cells pathways activation. These results suggest that the reactive microgliosis intensity during AD might depend on the disease progression and consequently on the Abeta conformation production. The recognition of Abeta by the formylpeptide chemotactic receptor 2 seems to be a starting point of the signaling cascade inducing an inflammatory state. [less ▲]

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See detailThe hematopoietic factor granulocyte-colony stimulating factor improves outcome in experimental spinal cord injury.
Pitzer, Claudia; Klussmann, Stefan; Krüger, Carola et al

in Journal of Neurochemistry (2010), 113

Granulocyte-colony stimulating factor (G-CSF) is a potent hematopoietic factor that drives differentiation of neutrophilic granulocytes. We have recently shown that G-CSF also acts as a neuronal growth ... [more ▼]

Granulocyte-colony stimulating factor (G-CSF) is a potent hematopoietic factor that drives differentiation of neutrophilic granulocytes. We have recently shown that G-CSF also acts as a neuronal growth factor, protects neurons in vitro and in vivo, and has regenerative potential in various neurological disease models. Spinal cord injury (SCI) following trauma or secondary to skeletal instability is a terrible condition with no effective therapies available at present. In this study, we show that the G-CSF receptor is up-regulated upon experimental SCI and that G-CSF improves functional outcome in a partial dissection model of SCI. G-CSF significantly decreases apoptosis in an experimental partial spinal transsection model in the mouse and increases expression of the anti-apoptotic G-CSF target gene Bcl-X(L). In vitro, G-CSF enhances neurite outgrowth and branching capacity of hippocampal neurons. In vivo, G-CSF treatment results in improved functional connectivity of the injured spinal cord as measured by Mn(2+)-enhanced MRI. G-CSF also increased length of the dorsal corticospinal tract and density of serotonergic fibers cranial to the lesion center. Mice treated systemically with G-CSF as well as transgenic mice over-expressing G-CSF in the CNS exhibit a strong improvement in functional outcome as measured by the BBB score and gridwalk analysis. We show that G-CSF improves outcome after experimental SCI by counteracting apoptosis, and enhancing connectivity in the injured spinal cord. We conclude that G-CSF constitutes a promising and feasible new therapy option for SCI. [less ▲]

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