Progressive degeneration of human mesencephalic neuron-derived cells triggered by dopamine-dependent oxidative stress is dependent on the mixed-lineage kinase pathway
(2005) In The Journal of Neuroscience 25(27). p.6329-6342- Abstract
- 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... (More)
- 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. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/233034
- author
- Lotharius, J ; Falsig, J ; van Beek, J ; Payne, S ; Dringen, R ; Brundin, Patrik LU and Leist, M
- organization
- publishing date
- 2005
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- SAPK, in vitro, reactive oxygen species, apoptosis, MLK, neurodegeneration
- in
- The Journal of Neuroscience
- volume
- 25
- issue
- 27
- pages
- 6329 - 6342
- publisher
- Society for Neuroscience
- external identifiers
-
- pmid:16000623
- wos:000230405000009
- scopus:21844442345
- ISSN
- 1529-2401
- DOI
- 10.1523/JNEUROSCI.1746-05.2005
- language
- English
- LU publication?
- yes
- additional info
- The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Neuronal Survival (013212041)
- id
- 5e72298d-f6f7-4baf-98a1-cc708696a59e (old id 233034)
- date added to LUP
- 2016-04-01 16:39:59
- date last changed
- 2023-10-31 10:44:27
@article{5e72298d-f6f7-4baf-98a1-cc708696a59e,
abstract = {{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.}},
author = {{Lotharius, J and Falsig, J and van Beek, J and Payne, S and Dringen, R and Brundin, Patrik and Leist, M}},
issn = {{1529-2401}},
keywords = {{SAPK; in vitro; reactive oxygen species; apoptosis; MLK; neurodegeneration}},
language = {{eng}},
number = {{27}},
pages = {{6329--6342}},
publisher = {{Society for Neuroscience}},
series = {{The Journal of Neuroscience}},
title = {{Progressive degeneration of human mesencephalic neuron-derived cells triggered by dopamine-dependent oxidative stress is dependent on the mixed-lineage kinase pathway}},
url = {{http://dx.doi.org/10.1523/JNEUROSCI.1746-05.2005}},
doi = {{10.1523/JNEUROSCI.1746-05.2005}},
volume = {{25}},
year = {{2005}},
}