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

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2012
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NeuroToxicology. 2012, 33(4), pp. 769-779. ISSN 0161-813X. eISSN 1872-9711. Available under: doi: 10.1016/j.neuro.2011.12.007
Zusammenfassung

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.

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570 Biowissenschaften, Biologie
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MPP+, dopamine, LUHMES, caspases, oxidative stress, Parkinson’s disease
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ISO 690PÖLTL, Dominik, Stefan SCHILDKNECHT, Christiaan KARREMAN, Marcel LEIST, 2012. Uncoupling of ATP-depletion and cell death in human dopaminergic neurons. In: NeuroToxicology. 2012, 33(4), pp. 769-779. ISSN 0161-813X. eISSN 1872-9711. Available under: doi: 10.1016/j.neuro.2011.12.007
BibTex
@article{Poltl2012-08Uncou-18066,
  year={2012},
  doi={10.1016/j.neuro.2011.12.007},
  title={Uncoupling of ATP-depletion and cell death in human dopaminergic neurons},
  number={4},
  volume={33},
  issn={0161-813X},
  journal={NeuroToxicology},
  pages={769--779},
  author={Pöltl, Dominik and Schildknecht, Stefan and Karreman, Christiaan and Leist, Marcel}
}
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