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High Content Screening in Neurodegenerative Diseases
Published on: January 6, 2012
DJ-1 protects against dopamine toxicity.
Nirit Lev1, Debby Ickowicz, Yael Barhum
1Department of Neurology, Felsenstein Medical Research Centre, Rabin Medical Centre, Tel Aviv University, Petah-Tikva, Israel. lev.nirit@gmail.com
Journal of Neural Transmission (Vienna, Austria : 1996)
|November 1, 2008
Summary
DJ-1 protein protects against dopamine toxicity, a key factor in Parkinson's disease (PD). This study reveals DJ-1 upregulation via the MAP kinase pathway as a protective response to oxidative stress in PD.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Parkinson's disease (PD) involves dopaminergic neuron loss.
- Dopamine generates toxic reactive oxygen species (ROS).
- DJ-1 mutations are linked to early-onset inherited PD.
Purpose of the Study:
- To investigate DJ-1's role in protecting against dopamine toxicity.
- To elucidate the mechanism of DJ-1 upregulation in response to oxidative stress.
Main Methods:
- Dopamine exposure in vitro and 6-hydroxydopamine administration in vivo.
- Manipulation of DJ-1 levels using overexpression and siRNA.
- Assessment of cell resistance to dopamine toxicity and intracellular ROS levels.
- Analysis of the MAP kinase pathway, including ERK 1, 2 activation.
Main Results:
- Dopamine exposure upregulated DJ-1 expression.
- DJ-1 overexpression enhanced cell resistance to dopamine toxicity and reduced ROS.
- siRNA-mediated reduction of DJ-1 decreased cellular resistance.
- In vivo striatal 6-hydroxydopamine administration also upregulated DJ-1.
- DJ-1 upregulation was mediated by MAP kinases, specifically ERK 1, 2 activation.
Conclusions:
- Oxidative stress from cytoplasmic dopamine triggers DJ-1 upregulation via the MAP kinase pathway.
- This mechanism explains how DJ-1 mutations contribute to PD.
- Modulating DJ-1 presents a potential neuroprotective strategy for Parkinson's disease.
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