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Goldberg MS, Pisani A, Haburcak M, Vortherms TA, Kitada T, Costa C, Tong Y, Martella G, Tscherter A, Martins A, Bernardi G, Roth BL, Pothos EN, Calabresi P, Shen J. Nigrostriatal dopaminergic deficits and hypokinesia caused by inactivation of the familial Parkinsonism-linked gene DJ-1. Neuron. 2005 Feb 17;45(4):489-96. PubMed.
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National Institute on Aging
Recessive mutations, like those in DJ-1 that are associated with Parkinsonism, are great candidates for making knockout alleles in mice to try and model the disease, as well as understand normal gene function. In this paper, Matt Goldberg, Jie Shen, and their colleagues have produced the first description of a DJ-1 knockout mouse, thus generating a potential model of these rare patients. They show alterations in dopaminergic function in the absence of cell loss in the nigra. This phenotype may be related to the small changes in the dopamine system reported by the same group in parkin mice, but the changes are more dramatic than in the previous model. We are hampered somewhat by the lack of pathology in the patients in being able to really assess how successful this model has been. Clearly this is not a full “PD” phenotype, as there is no TH-positive cell loss, but the fact that there are measurable differences indicates that this might be a workable model if it can be replicated.
What needs further clarification is why DJ-1 would have an effect on synaptic events. As several people have pointed out, this protein has such a range of possible functions that it is difficult to immediately see what role it plays at the synapse. It will be nice to see that replacement of the knocked-out DJ-1 rescues the effects, and to investigate whether the known potential for oxidation of the protein is important. There has been some controversy, but it is likely that oxidation of one or more cysteines is important and it would be possible to investigate whether cysteine mutants can perform this normal function of DJ-1.
Another question that might be answered is: How promiscuous is DJ-1 on synaptic function—is it specific for dopamine or does it generally affect all synapses? The data in the paper showing that D2 receptors seem to be preferentially affected hint at specificity, but it would be good to see this confirmed.
Finally, it will be really interesting to see how these mice age and whether there is any effect of crossing them onto other recessive backgrounds (i.e., parkin and PINK1). Do these genes work in tandem to cause additive amounts of disruption, eventually leading to more substantial neuronal loss? Or are they truly a pathway, with each having a sequential effect? Having a model like this gives us perhaps our first opportunity to start to ask some of these questions in a relevant physiological context.
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