Oxidant stress evoked by pacemaking in dopaminergic neurons is attenuated by DJ-1 (original) (raw)
- Letter
- Published: 10 November 2010
- Javier Sanchez-Padilla1,
- David Wokosin1,
- Jyothisri Kondapalli2,
- Ema Ilijic1,
- Paul T. Schumacker2 &
- …
- D. James Surmeier1
Nature volume 468, pages 696–700 (2010)Cite this article
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A Corrigendum to this article was published on 20 May 2015
Abstract
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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References
- Albin, R. L., Young, A. B. & Penney, J. B. The functional anatomy of disorders of the basal ganglia. Trends Neurosci. 18, 63–64 (1995)
Article CAS Google Scholar - Schapira, A. H. Mitochondria in the aetiology and pathogenesis of Parkinson’s disease. Lancet Neurol. 7, 97–109 (2008)
Article CAS Google Scholar - Puopolo, M., Raviola, E. & Bean, B. P. Roles of subthreshold calcium current and sodium current in spontaneous firing of mouse midbrain dopamine neurons. J. Neurosci. 27, 645–656 (2007)
Article CAS Google Scholar - Chan, C. S. et al. ‘Rejuvenation’ protects neurons in mouse models of Parkinson’s disease. Nature 447, 1081–1086 (2007)
Article ADS CAS Google Scholar - Khaliq, Z. M. & Bean, B. P. Pacemaking in dopaminergic ventral tegmental area neurons: depolarizing drive from background and voltage-dependent sodium conductances. J. Neurosci. 30, 7401–7413 (2010)
Article CAS Google Scholar - Guzman, J. N., Sanchez-Padilla, J., Chan, C. S. & Surmeier, D. J. Robust pacemaking in substantia nigra dopaminergic neurons. J. Neurosci. 29, 11011–11019 (2009)
Article CAS Google Scholar - Dooley, C. T. et al. Imaging dynamic redox changes in mammalian cells with green fluorescent protein indicators. J. Biol. Chem. 279, 22284–22293 (2004)
Article CAS Google Scholar - Matlib, M. A. et al. Oxygen-bridged dinuclear ruthenium amine complex specifically inhibits Ca2+ uptake into mitochondria in vitro and in situ in single cardiac myocytes. J. Biol. Chem. 273, 10223–10231 (1998)
Article CAS Google Scholar - Nicholls, D. G. & Ferguson, S. J. Bioenergetics 3 (Academic, 2002)
Google Scholar - Kahle, P. J., Waak, J. & Gasser, T. DJ-1 and prevention of oxidative stress in Parkinson’s disease and other age-related disorders. Free Radic. Biol. Med. 47, 1354–1361 (2009)
Article CAS Google Scholar - Ehrenberg, B., Montana, V., Wei, M. D., Wuskell, J. P. & Loew, L. M. Membrane potential can be determined in individual cells from the Nernstian distribution of cationic dyes. Biophys. J. 53, 785–794 (1988)
Article CAS Google Scholar - Rasola, A. & Bernardi, P. The mitochondrial permeability transition pore and its involvement in cell death and in disease pathogenesis. Apoptosis 12, 815–833 (2007)
Article CAS Google Scholar - Krauss, S., Zhang, C. Y. & Lowell, B. B. The mitochondrial uncoupling-protein homologues. Nature Rev. Mol. Cell Biol. 6, 248–261 (2005)
Article CAS Google Scholar - Brand, M. D. et al. Mitochondrial superoxide and aging: uncoupling-protein activity and superoxide production. Biochem. Soc. Symp. 71, 203–213 (2004)
Article CAS Google Scholar - Andrews, Z. B. et al. Uncoupling protein-2 is critical for nigral dopamine cell survival in a mouse model of Parkinson’s disease. J. Neurosci. 25, 184–191 (2005)
Article CAS Google Scholar - Zhang, C. Y. et al. Genipin inhibits UCP2-mediated proton leak and acutely reverses obesity- and high glucose-induced beta cell dysfunction in isolated pancreatic islets. Cell Metab. 3, 417–427 (2006)
Article CAS Google Scholar - Echtay, K. S. et al. Superoxide activates mitochondrial uncoupling proteins. Nature 415, 96–99 (2002)
Article ADS CAS Google Scholar - Papa, S. & Skulachev, V. P. Reactive oxygen species, mitochondria, apoptosis and aging. Mol. Cell. Biochem. 174, 305–319 (1997)
Article CAS Google Scholar - Canet-Aviles, R. M. et al. The Parkinson’s disease protein DJ-1 is neuroprotective due to cysteine-sulfinic acid-driven mitochondrial localization. Proc. Natl Acad. Sci. USA 101, 9103–9108 (2004)
Article ADS CAS Google Scholar - Bonifati, V. et al. Mutations in the DJ-1 gene associated with autosomal recessive early-onset Parkinsonism. Science 299, 256–259 (2003)
Article ADS CAS Google Scholar - Cookson, M. R. DJ-1, PINK1, and their effects on mitochondrial pathways. Mov. Disord. 25 (suppl. 1). S44–S48 (2010)
Article Google Scholar - Bender, A. et al. High levels of mitochondrial DNA deletions in substantia nigra neurons in aging and Parkinson disease. Nature Genet. 38, 515–517 (2006)
Article MathSciNet CAS Google Scholar - Bender, A. et al. Dopaminergic midbrain neurons are the prime target for mitochondrial DNA deletions. J. Neurol. 255, 1231–1235 (2008)
Article Google Scholar - Krishnan, K. J., Greaves, L. C., Reeve, A. K. & Turnbull, D. M. Mitochondrial DNA mutations and aging. Ann. NY Acad. Sci. 1100, 227–240 (2007)
Article ADS CAS Google Scholar - Nicholls, D. G. Oxidative stress and energy crises in neuronal dysfunction. Ann. NY Acad. Sci. 1147, 53–60 (2008)
Article ADS CAS Google Scholar - Eisenberg, M. J., Brox, A. & Bestawros, A. N. Calcium channel blockers: an update. Am. J. Med. 116, 35–43 (2004)
Article CAS Google Scholar - Becker, C., Jick, S. S. & Meier, C. R. Use of antihypertensives and the risk of Parkinson disease. Neurology 70, 1438–1444 (2008)
Article CAS Google Scholar - Ritz, B. et al. L-type calcium channel blockers and Parkinson disease in Denmark. Ann. Neurol. 67, 600–606, 10.1002/ana.21937 (2010)
Article CAS PubMed PubMed Central Google Scholar - Son, J. H. et al. Neuroprotection and neuronal differentiation studies using substantia nigra dopaminergic cells derived from transgenic mouse embryos. J. Neurosci. 19, 10–20 (1999)
Article CAS Google Scholar - Bookout, A. L., Cummins, C. L., Mangelsdorf, D. J., Pesola, J. M. & Kramer, M. F. High-throughput real-time quantitative reverse transcription PCR. Curr. Protoc. Mol. Biol. Chapter 15, Unit 15 18. (2006)
- Schmittgen, T. D. & Livak, K. J. Analyzing real-time PCR data by the comparative C T method. Nature Protocols 3, 1101–1108 (2008)
Article CAS Google Scholar - Tian, X., Kai, L., Hockberger, P. E., Wokosin, D. L. & Surmeier, D. J. MEF-2 regulates activity-dependent spine loss in striatopallidal medium spiny neurons. Mol. Cell. Neurosci. 44, 94–108 (2010)
Article CAS Google Scholar - Fath, T., Ke, Y. D., Gunning, P., Gotz, J. & Ittner, L. M. Primary support cultures of hippocampal and substantia nigra neurons. Nature Protocols 4, 78–85 (2009)
Article CAS Google Scholar
Acknowledgements
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.).
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Authors and Affiliations
- Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, 60611, Illinois, USA
Jaime N. Guzman, Javier Sanchez-Padilla, David Wokosin, Ema Ilijic & D. James Surmeier - Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, 60611, Illinois, USA
Jyothisri Kondapalli & Paul T. Schumacker
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- Jaime N. Guzman
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Contributions
D.J.S. was responsible for the overall direction of the experiments, analysis of data, construction of figures and communication of the results. J.N.G. and J.S.-P. were responsible for the design and execution of experiments, as well as the analysis of results. D.W. provided expertise on optical approaches. E.I. conducted the immunocytochemical experiments. P.T.S. and J.K. were responsible for the generation of the TH-mito-roGFP mice; they also participated in the design, analysis and communication of the results.
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Correspondence toD. James Surmeier.
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Supplementary Figures
The file contains Supplementary Figures 1-7 with legends. (PDF 2278 kb)
Supplementary Movie 1
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). https://doi.org/10.1038/nature09536
- Received: 17 January 2010
- Accepted: 29 September 2010
- Published: 10 November 2010
- Issue Date: 02 December 2010
- DOI: https://doi.org/10.1038/nature09536
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