Abstract
Mitochondrial oxidant stress is widely viewed as being critical to pathogenesis in Parkinson's disease. But the origins of this stress are poorly defined. One possibility is that it arises from the metabolic demands associated with regenerative activity. To test this hypothesis, we characterized neurons in the dorsal motor nucleus of the vagus (DMV), a population of cholinergic neurons that show signs of pathology in the early stages of Parkinson's disease, in mouse brain slices. DMV neurons were slow, autonomous pacemakers with broad spikes, leading to calcium entry that was weakly buffered. Using a transgenic mouse expressing a redox-sensitive optical probe targeted to the mitochondrial matrix, we found that calcium entry during pacemaking created a basal mitochondrial oxidant stress. Knocking out DJ-1 (also known as PARK7), a gene associated with early-onset Parkinson's disease, exacerbated this stress. These results point to a common mechanism underlying mitochondrial oxidant stress in Parkinson's disease and a therapeutic strategy to ameliorate it.
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Acknowledgements
We thank Y. Chen, S. Ulrich, K. Saporito and D. Ren for their expert technical help. We thank R. Miller for valuable discussions. This work was supported by grants from the Hartman Foundation, the IDP Foundation, the Picower Foundation, the US National Institutes of Health (P50 NS047085 and T32 NS041234) and the Department of Defense (W81XWH-11-1-051) to D.J.S.
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J.A.G. designed and conducted the experiments and analyzed the data. J.N.G. conducted some of the control roGFP experiments. C.M.E. and E.I. conducted the histological experiments. J.K. and J.S.-P. generated the CMV–mito-roGFP and DJ-1−/− mice. D.J.S. was responsible for the overall direction of the experiments. J.A.G. and D.J.S. prepared the manuscript and illustrations.
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Goldberg, J., Guzman, J., Estep, C. et al. Calcium entry induces mitochondrial oxidant stress in vagal neurons at risk in Parkinson's disease. Nat Neurosci 15, 1414–1421 (2012). https://doi.org/10.1038/nn.3209
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DOI: https://doi.org/10.1038/nn.3209
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