Uncoupling of ATP-depletion and cell death in human dopaminergic neurons


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PÖLTL, Dominik, Stefan SCHILDKNECHT, Christiaan KARREMAN, Marcel LEIST, 2012. Uncoupling of ATP-depletion and cell death in human dopaminergic neurons. In: NeuroToxicology. 33(4), pp. 769-779. ISSN 0161-813X. eISSN 1872-9711

@article{Poltl2012-08Uncou-18066, title={Uncoupling of ATP-depletion and cell death in human dopaminergic neurons}, year={2012}, doi={10.1016/j.neuro.2011.12.007}, number={4}, volume={33}, issn={0161-813X}, journal={NeuroToxicology}, pages={769--779}, author={Pöltl, Dominik and Schildknecht, Stefan and Karreman, Christiaan and Leist, Marcel} }

<rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" xmlns:bibo="http://purl.org/ontology/bibo/" xmlns:dc="http://purl.org/dc/elements/1.1/" xmlns:dcterms="http://purl.org/dc/terms/" xmlns:xsd="http://www.w3.org/2001/XMLSchema#" > <rdf:Description rdf:about="https://kops.uni-konstanz.de/rdf/resource/123456789/18066"> <dcterms:title>Uncoupling of ATP-depletion and cell death in human dopaminergic neurons</dcterms:title> <dc:language>eng</dc:language> <dc:contributor>Schildknecht, Stefan</dc:contributor> <dcterms:available rdf:datatype="http://www.w3.org/2001/XMLSchema#dateTime">2012-08-14T11:33:37Z</dcterms:available> <dc:contributor>Pöltl, Dominik</dc:contributor> <dcterms:rights rdf:resource="http://nbn-resolving.org/urn:nbn:de:bsz:352-20140905103605204-4002607-1"/> <dc:creator>Karreman, Christiaan</dc:creator> <bibo:uri rdf:resource="http://kops.uni-konstanz.de/handle/123456789/18066"/> <dc:contributor>Karreman, Christiaan</dc:contributor> <dcterms:bibliographicCitation>Publ. in: Neurotoxicology ; 33 (2012), 4. - S. 769-779</dcterms:bibliographicCitation> <dc:date rdf:datatype="http://www.w3.org/2001/XMLSchema#dateTime">2012-08-14T11:33:37Z</dc:date> <dc:rights>deposit-license</dc:rights> <dcterms:abstract xml:lang="eng">The mitochondrial inhibitor 1-methyl-4-phenylpyridinium (MPP(+)) is the toxicologically relevant metabolite of 1-methyl-4-phenyltetrahydropyridine (MPTP), which causes relatively selective degeneration of dopaminergic neurons in the substantia nigra. Dopaminergic LUHMES cells were used to investigate whether ATP-depletion can be uncoupled from cell death as a downstream event in these fully post-mitotic human neurons. Biochemical assays indicated that in the homogeneously differentiated cell cultures, MPP(+) was taken up by the dopamine transporter (DAT). MPP(+) then triggered oxidative stress and caspase activation, as well as ATP-depletion followed by cell death. Enhanced survival of the neurons in the presence of agents interfering with mitochondrial pathology, such as the fission inhibitor Mdivi-1 or a Bax channel blocker suggested a pivotal role of mitochondria in this model. However, these compounds did not prevent cellular ATP-depletion. To further investigate whether cells could be rescued despite respiratory chain inhibition by MPP(+), we have chosen a diverse set of pharmacological inhibitors well-known to interfere with MPP(+) toxicity. The antioxidant ascorbate, the iron chelator desferoxamine, the stress kinase inhibitor CEP1347, and different caspase inhibitors reduced cell death, but allowed ATP-depletion in protected cells. None of these compounds interfered with MPP(+) accumulation in the cells. These findings suggest that ATP-depletion, as the initial mitochondrial effect of MPP(+), requires further downstream processes to result in neuronal death. These processes may form self-enhancing signaling loops, that aggravate an initial energetic impairment and eventually determine cell fate.</dcterms:abstract> <dc:creator>Leist, Marcel</dc:creator> <dc:contributor>Leist, Marcel</dc:contributor> <dcterms:issued>2012-08</dcterms:issued> <dc:creator>Schildknecht, Stefan</dc:creator> <dc:creator>Pöltl, Dominik</dc:creator> </rdf:Description> </rdf:RDF>

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