How Do Mutations in DJ-1 Cause Parkinson’s Disease?

Abstracts & Commentary

Synopsis: Dopamine neurons derived from in vitro differentiated DJ-1 deficient embryonic stem cells showed decreased survival and increased sensitivity to oxidative stress.

Sources: Shendelman, et al. DJ-1 Is a Redox-Dependent Molecular Chaperone That Inhibits a-Synuclein Aggregate Information. PLoS Biology. 2004;2(11):e362; Martinat, et al. Sensitivity To Oxidative Stress in DJ-1 Deficient Dopamine Neurons: An ES-Derived Cell Model of Primary Parkinsonism. PLoS Biology. 2004;2(11):e327.

Parkinson’s disease is characterized by degeneration of mid-brain dopaminergic neurons, leading to a progressive movement disorder. An autosomal recessive form of Parkinson’s Disease was recently identified. This was caused by homozygous mutations in DJ-1 in 2 families. The mechanism by which DJ-1 produces Parkinson’s Disease however, is as yet unknown.

In 2 recent papers published in a new freely available online journal, the mechanisms by which DJ-1 lesions produce Parkinson’s Disease were evaluated. Interestingly, there appears to be a link between a chaperone function of DJ-1, as well as oxidative damage. DJ-1 was shown to function as a redox-sensitive molecular chaperone that is activated in an oxidative environment. The DJ-1 chaperone activity in vivo extends to alpha-synuclein, a protein implicated in autosomal dominant Parkinson’s Disease.

In the accompanying paper, Shendelman and colleagues utilized a new technique to evaluate the function of DJ-1 in human dopaminergic embryonic stem cells. Human embryonic stem cells were cultured and differentiated into dopaminergic stem cells by culturing them on a glial stroma. Shendelman et al found that the embryonic stem cells deficient in DJ-1 display increased sensitivity to oxidative stress, as well as proteosomal inhibition. The accumulation of reactive oxygen species in toxin-treated DJ-1 deficient cells was initially normal, but they were unable to cope with the consequent damage, leading to apoptotic cell death. The cells were abnormally sensitive to 6-hydroxy-dopamine. Dopamine neurons derived from in vitro differentiated DJ-1 deficient embryonic stem cells showed decreased survival and increased sensitivity to oxidative stress.

Commentary

These 2 papers provide a mechanism by which DJ-1 mutations may cause Parkinson’s Disease. They show that DJ-1 is important in protecting against oxidative damage. However, its primary effect is to act as a molecular chaperone. It therefore links oxidative damage to protein aggregation. It appears that DJ-1 normally functions in an oxidative stress environment to inhibit protein aggregation. As such, this protein links 2 fundamental processes which are implicated in Parkinson’s Disease pathogenesis. —M. Flint Beal

M. Flint Beal, MD Professor and Chairman; Department of Neurology; Cornell University Medical College New York, NY is Editor of Neurology Alert.