Parkinson’s disease is a pervasive, ageing-related neurodegenerative disease the cardinal motor symptoms of which reflect the loss of a small group of neurons, the dopaminergic neurons in the substantia nigra pars compacta1 (SNc). Mitochondrial oxidant stress is widely viewed as being responsible for this loss2, but why these particular neurons should be stressed is a mystery. Here we show, using transgenic mice that expressed a redox-sensitive variant of green fluorescent protein targeted to the mitochondrial matrix, that the engagement of plasma membrane L-type calcium channels during normal autonomous pacemaking created an oxidant stress that was specific to vulnerable SNc dopaminergic neurons. The oxidant stress engaged defences that induced transient, mild mitochondrial depolarization or uncoupling. The mild uncoupling was not affected by deletion of cyclophilin D, which is a component of the permeability transition pore, but was attenuated by genipin and purine nucleotides, which are antagonists of cloned uncoupling proteins. Knocking out DJ-1 (also known as PARK7 in humans and Park7 in mice), which is a gene associated with an early-onset form of Parkinson’s disease, downregulated the expression of two uncoupling proteins (UCP4 (SLC25A27) and UCP5 (SLC25A14)), compromised calcium-induced uncoupling and increased oxidation of matrix proteins specifically in SNc dopaminergic neurons. Because drugs approved for human use can antagonize calcium entry through L-type channels, these results point to a novel neuroprotective strategy for both idiopathic and familial forms of Parkinson’s disease.
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We acknowledge the technical help of P. Hockberger, N. Schwarz, S. Ulrich, Y. Chen, C. S. Chan, D. Dryanovski and K. Saporito. We acknowledge S. Chan for supplying quantitative PCR primer sets. We acknowledge the gifts of DJ-1 knockout mice from T. and V. Dawson, Ucp2 knockout mice from D. Kong and B. Lowell, and cyclophilin D knockout mice from S. J. Korsmeyer. This work was supported by the Picower Foundation, the Hartman Foundation, the Falk Trust, the Parkinson’s Disease Foundation, NIH grants NS047085 (D.J.S.), NS 054850 (D.J.S.), K12GM088020 (J.S.-P.), HL35440 (P.T.S.) and RR025355 (P.T.S.), and DOD contract W81XWH-07-1-0170 (D.J.S.).
The authors declare no competing financial interests.
The file contains Supplementary Figures 1-7 with legends. (PDF 2278 kb)
The movie shows TMRM fluorescence in an SNc dopaminergic neuron before and after bath application of isradipine (5 μM).Note the decreased flickering after application of isradipine. Similar results were seen in all of the neurons examined (n≳20). (MOV 12251 kb)
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Guzman, J., Sanchez-Padilla, J., Wokosin, D. et al. Oxidant stress evoked by pacemaking in dopaminergic neurons is attenuated by DJ-1. Nature 468, 696–700 (2010) doi:10.1038/nature09536
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