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The Journal of Neuroscience, July 6, 2005, 25(27):6329-6342; doi:10.1523/JNEUROSCI.1746-05.2005

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Neurobiology of Disease
Progressive Degeneration of Human Mesencephalic Neuron-Derived Cells Triggered by Dopamine-Dependent Oxidative Stress Is Dependent on the Mixed-Lineage Kinase Pathway

Julie Lotharius,¹ Jeppe Falsig,^1,2 Johan van Beek,¹ Sarah Payne,³ Ralf Dringen,⁴ Patrik Brundin,⁵ and Marcel Leist¹

¹Department of Disease Biology, H. Lundbeck A/S, 2500 Valby, Denmark, ²Institute of Neuropathology, University Hospital Zurich, CH-8091 Zurich, Switzerland, ³Cellomics Europe, Old Amersham HP7 0UT, United Kingdom, ⁴Faculty 2 (Biology/Chemistry), University of Bremen, D-28334 Bremen, Germany, and ⁵Section for Neuronal Survival, Wallenberg Neuroscience Center, Department of Physiological Sciences, Lund University, 221 84 Lund, Sweden

Models of Parkinson's disease (PD) based on selective neuronal death have been used to study pathogenic mechanisms underlying nigral cell death and in some instances to develop symptomatic therapies. For validation of putative neuroprotectants, a model is desirable in which the events leading to neurodegeneration replicate those occurring in the disease. We developed a human in vitro model of PD based on the assumption that dysregulated cytoplasmic dopamine levels trigger cell loss in this disorder. Differentiated human mesencephalic neuron-derived cells were exposed to methamphetamine (METH) to promote cytoplasmic dopamine accumulation. In the presence of elevated iron concentrations, as observed in PD, increased cytosolic dopamine led to oxidative stress, c-Jun N-terminal kinase (JNK) pathway activation, neurite degeneration, and eventually apoptosis. We examined the role of the mixed-lineage kinases (MLKs) in this complex degenerative cascade by using the potent inhibitor 3,9-bis[(ethylthio)methyl]-K-252a (CEP1347). Inhibition of MLKs not only prevented FeCl²⁺/METH-induced JNK activation and apoptosis but also early events such as neurite degeneration and oxidative stress. This broad neuroprotective action of CEP1347 was associated with increased expression of an oxidative stress-response modulator, activating transcription factor 4. As a functional consequence, transcription of the cystine/glutamate and glycine transporters, cellular cystine uptake and intracellular levels of the redox buffer glutathione were augmented. In conclusion, this new human model of parkinsonian neurodegeneration has the potential to yield new insights into neurorestorative therapeutics and suggests that enhancement of cytoprotective mechanisms, in addition to blockade of apoptosis, may be essential for disease modulation.

Key words: in vitro; reactive oxygen species; SAPK; neurodegeneration; apoptosis; MLK

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Received Jan 16, 2005; revised May 25, 2005; accepted May 26, 2005.

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