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Calcium entry induces mitochondrial oxidant stress in vagal neurons at risk in Parkinson's disease

Nature Neuroscience volume 15, pages 1414–1421 (2012)Cite this article

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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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Figure 1: Autonomous discharge in cholinergic neurons of the DMV.
Figure 2: Role of sodium currents in the pacemaking of cholinergic DMV neurons.
Figure 3: Calcium currents during the pacemaking cycle in DMV neurons.
Figure 4: 2PLSM calcium imaging reveals that calcium dynamics are dominated by spike-associated influx.
Figure 5: Contribution of Cav1 channels to discharge patterns and ambient calcium levels in DMV neurons.
Figure 6: DMV neurons have a low endogenous buffering capacity relative to dopaminergic VTA neurons.
Figure 7: Mitochondria in DMV neurons are normally oxidized and are reduced by pre-incubation in isradipine.

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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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Authors and Affiliations

  1. Department of Physiology, Feinberg School of Medicine, Northwestern University Chicago, Illinois, USA

    Joshua A Goldberg, Jaime N Guzman, Chad M Estep, Ema Ilijic, Jyothisri Kondapalli, Javier Sanchez-Padilla & D James Surmeier

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Contributions

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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Correspondence to D James Surmeier.

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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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