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Despite the well-characterized cellular basis of Parkinson's disease -- the degeneration of dopamine-production neurons -- the molecular mechanisms responsible for the neurodegeneration remain unknown. Part of the challenge is finding a model that can adequately mimic the loss of dopamine cells. In two papers published in PLoS Biology, Asa Abeliovich and colleagues make the case that a model based on mouse embryonic stem cells offers a promising platform for dissecting the disease mechanism of Parkinson's.
Working with these cells, the researchers created dopamine neurons deficient in DJ-1, a gene mutated in an inherited form of Parkinson's. They report that DJ-1-deficient cells -- and especially DJ-1-deficient dopamine neurons -- display heightened sensitivity to oxidative stress, caused by products of oxygen metabolism that react with and damage cellular components like proteins and DNA. In a second paper, they link DJ-1 dysfunction to the aggregation of alpha-synuclein, a hallmark of Parkinson's neuropathology.
Oxidative stress has long been associated with neuronal cell death and neurodegenerative diseases like Parkinson's. Proving a causal relationship between oxidative stress and neurodegeneration, however, requires establishing a molecular mechanism. These results support a link between oxidative damage and disease, and provide a tractable model for both studying the molecular mechanisms of neurodegenerative disease and screening potential neuroprotectant drugs. The authors are hoping to extend their work to human embryonic stem cells, but their work is limited by the availability of such cells under the current NIH guidelines.
Citations:
1) Martinat C, et al. (2004) Sensitivity to Oxidative Stress in DJ-1-Deficient Dopamine Neurons: An ES-Derived Cell Model of Primary Parkinsonism. PLoS Biol 2 (11): e327.
2) Shendelman S, et al. (2004) DJ-1 Is a Redox-Dependent Molecular Chaperone that Inhibits a-Synuclein Aggregate Formation. PLoS Biol 2 (11): e362.
CONTACT:
Asa Abeliovich
Taub Institute for the Aging Brain
New York, NY USA
1-212-305-1150
1-212-305-5498 (fax)
aa900@columbia.edu
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Journal
PLoS Biology