Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

‘Rejuvenation’ protects neurons in mouse models of Parkinson’s disease

Nature volume 447, pages 1081–1086 (2007)Cite this article

Abstract

Why dopamine-containing neurons of the brain’s substantia nigra pars compacta die in Parkinson’s disease has been an enduring mystery. Our studies suggest that the unusual reliance of these neurons on L-type Cav1.3 Ca2+ channels to drive their maintained, rhythmic pacemaking renders them vulnerable to stressors thought to contribute to disease progression. The reliance on these channels increases with age, as juvenile dopamine-containing neurons in the substantia nigra pars compacta use pacemaking mechanisms common to neurons not affected in Parkinson’s disease. These mechanisms remain latent in adulthood, and blocking Cav1.3 Ca2+ channels in adult neurons induces a reversion to the juvenile form of pacemaking. Such blocking (‘rejuvenation’) protects these neurons in both in vitro and in vivo models of Parkinson’s disease, pointing to a new strategy that could slow or stop the progression of the disease.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: SNc dopaminergic neurons are Ca v1.3-Ca 2+-channel-dependent pacemakers.
Figure 2: Pacemaking mechanisms in SNc dopaminergic neurons are developmentally regulated and sensitive to Ca v1.3 deletion.
Figure 3: Cav1.3 channel blockade induces a reversion to a juvenile form of Na+ /HCN-channel-dependent pacemaking.
Figure 4: Pacemaking currents govern dendritic Ca2+ concentrations.
Figure 5: Rejuvenation of SNc dopaminergic neurons protects them against the mitochondrial toxin rotenone and chronic MPTP treatment.

Similar content being viewed by others

References

  1. Braak, H., Ghebremedhin, E., Rub, U., Bratzke, H. & Del Tredici, K. Stages in the development of Parkinson’s disease-related pathology. Cell Tissue Res. 318, 121–134 (2004)

    Article  PubMed  Google Scholar 

  2. Hornykiewicz, O. Dopamine (3-hydroxytyramine) and brain function. Pharmacol. Rev. 18, 925–964 (1966)

    CAS  PubMed  Google Scholar 

  3. Riederer, P. & Wuketich, S. Time course of nigrostriatal degeneration in Parkinson’s disease. A detailed study of influential factors in human brain amine analysis. J. Neural Transm. 38, 277–301 (1976)

    Article  CAS  PubMed  Google Scholar 

  4. Abou-Sleiman, P. M., Muqit, M. M. & Wood, N. W. Expanding insights of mitochondrial dysfunction in Parkinson’s disease. Nature Rev. Neurosci. 7, 207–219 (2006)

    Article  CAS  Google Scholar 

  5. Zhang, L. et al. Mitochondrial localization of the Parkinson’s disease related protein DJ-1: Implications for pathogenesis. Hum. Mol. Genet. 14, 2063–2073 (2005)

    Article  CAS  PubMed  Google Scholar 

  6. Kwong, J. Q., Beal, M. F. & Manfredi, G. The role of mitochondria in inherited neurodegenerative diseases. J. Neurochem. 97, 1659–1675 (2006)

    Article  CAS  PubMed  Google Scholar 

  7. Bender, A. et al. High levels of mitochondrial DNA deletions in substantia nigraneurons in aging and Parkinson disease. Nature Genet. 38, 515–517 (2006)

    Article  CAS  PubMed  Google Scholar 

  8. Kraytsberg, Y. et al. Mitochondrial DNA deletions are abundant and cause functional impairment in aged human substantia nigra neurons. Nature Genet. 38, 518–520 (2006)

    Article  CAS  PubMed  Google Scholar 

  9. Swerdlow, R. H. et al. Origin and functional consequences of the complex I defect in Parkinson’s disease. Ann. Neurol. 40, 663–671 (1996)

    Article  CAS  PubMed  Google Scholar 

  10. Dawson, T. M. & Dawson, V. L. Molecular pathways of neurodegeneration in Parkinson’s disease. Science 302, 819–822 (2003)

    Article  ADS  CAS  PubMed  Google Scholar 

  11. Greenamyre, J. T. & Hastings, T. G. Biomedicine. Parkinson’s—divergent causes, convergent mechanisms. Science 304, 1120–1122 (2004)

    Article  CAS  PubMed  Google Scholar 

  12. Zecca, L., Zucca, F. A., Wilms, H. & Sulzer, D. Neuromelanin of the substantia nigra: A neuronal black hole with protective and toxic characteristics. Trends Neurosci. 26, 578–580 (2003)

    Article  CAS  PubMed  Google Scholar 

  13. Michel, P. P. & Hefti, F. Toxicity of 6-hydroxydopamine and dopamine for dopaminergic neurons in culture. J. Neurosci. Res. 26, 428–435 (1990)

    Article  CAS  PubMed  Google Scholar 

  14. Kish, S. J., Shannak, K. & Hornykiewicz, O. Uneven pattern of dopamine loss in the striatum of patients with idiopathic Parkinson’s disease. Pathophysiologic and clinical implications. N. Engl. J. Med. 318, 876–880 (1988)

    Article  CAS  PubMed  Google Scholar 

  15. Hasbani, D. M., Perez, F. A., Palmiter, R. D. & O’Malley, K. L. Dopamine depletion does not protect against acute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxicity in vivo. J. Neurosci. 25, 9428–9433 (2005)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Fahn, S. Does levodopa slow or hasten the rate of progression of Parkinson’s disease? J. Neurol. 252 (Suppl. 4). IV37–IV42 (2005)

    Article  PubMed  CAS  Google Scholar 

  17. Mercuri, N. B. et al. Effects of dihydropyridine calcium antagonists on rat midbrain dopaminergic neurones. Br. J. Pharmacol. 113, 831–838 (1994)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Nedergaard, S., Flatman, J. A. & Engberg, I. Nifedipine- and omega-conotoxin-sensitive Ca2+ conductances in guinea-pig substantia nigra pars compacta neurones. J. Physiol. (Lond.) 466, 727–747 (1993)

    CAS  Google Scholar 

  19. Shepard, P. D. & Stump, D. Nifedipine blocks apamin-induced bursting activity in nigral dopamine-containing neurons. Brain Res. 817, 104–109 (1999)

    Article  CAS  PubMed  Google Scholar 

  20. Xu, W. & Lipscombe, D. Neuronal CaV1.3α1 L-type channels activate at relatively hyperpolarized membrane potentials and are incompletely inhibited by dihydropyridines. J. Neurosci. 21, 5944–5951 (2001)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Olson, P. A. et al. G-protein-coupled receptor modulation of striatal CaV1.3 L-type Ca2+ channels is dependent on a Shank-binding domain. J. Neurosci. 25, 1050–1062 (2005)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Koschak, A. et al. α1D (Cav1.3) subunits can form L-type Ca2+ channels activating at negative voltages. J. Biol. Chem. 276, 22100–22106 (2001)

    Article  CAS  PubMed  Google Scholar 

  23. Scholze, A., Plant, T. D., Dolphin, A. C. & Nurnberg, B. Functional expression and characterization of a voltage-gated CaV1.3 (α1D) calcium channel subunit from an insulin-secreting cell line. Mol. Endocrinol. 15, 1211–1221 (2001)

    CAS  PubMed  Google Scholar 

  24. Surmeier, D. J., Mercer, J. N. & Chan, C. S. Autonomous pacemakers in the basal ganglia: Who needs excitatory synapses anyway? Curr. Opin. Neurobiol. 15, 312–318 (2005)

    Article  CAS  PubMed  Google Scholar 

  25. Zolles, G. et al. Pacemaking by HCN channels requires interaction with phosphoinositides. Neuron 52, 1027–1036 (2006)

    Article  CAS  PubMed  Google Scholar 

  26. Neuhoff, H., Neu, A., Liss, B. & Roeper, J. Ih channels contribute to the different functional properties of identified dopaminergic subpopulations in the midbrain. J. Neurosci. 22, 1290–1302 (2002)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Beal, M. F. Excitotoxicity and nitric oxide in Parkinson’s disease pathogenesis. Ann. Neurol. 44, S110–S114 (1998)

    Article  CAS  PubMed  Google Scholar 

  28. Coyle, J. T. & Puttfarcken, P. Oxidative stress, glutamate, and neurodegenerative disorders. Science 262, 689–695 (1993)

    Article  ADS  CAS  PubMed  Google Scholar 

  29. Krieger, C. & Duchen, M. R. Mitochondria, Ca2+ and neurodegenerative disease. Eur. J. Pharmacol. 447, 177–188 (2002)

    Article  CAS  PubMed  Google Scholar 

  30. Verkhratsky, A. Physiology and pathophysiology of the calcium store in the endoplasmic reticulum of neurons. Physiol. Rev. 85, 201–279 (2005)

    Article  CAS  PubMed  Google Scholar 

  31. Dauer, W. & Przedborski, S. Parkinson’s disease: mechanisms and models. Neuron 39, 889–909 (2003)

    Article  CAS  PubMed  Google Scholar 

  32. Phinney, A. L. et al. Enhanced sensitivity of dopaminergic neurons to rotenone-induced toxicity with aging. Parkinsonism Relat. Disord. 12, 228–238 (2006)

    Article  PubMed  Google Scholar 

  33. Betarbet, R. et al. Chronic systemic pesticide exposure reproduces features of Parkinson’s disease. Nature Neurosci. 3, 1301–1306 (2000)

    Article  CAS  PubMed  Google Scholar 

  34. Jiang, Q., Yan, Z. & Feng, J. Activation of group III metabotropic glutamate receptors attenuates rotenone toxicity on dopaminergic neurons through a microtubule-dependent mechanism. J. Neurosci. 26, 4318–4328 (2006)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Bywood, P. T. & Johnson, S. M. Mitochondrial complex inhibitors preferentially damage substantia nigra dopamine neurons in rat brain slices. Exp. Neurol. 179, 47–59 (2003)

    Article  CAS  PubMed  Google Scholar 

  36. Przedborski, S. & Vila, M. The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model: A tool to explore the pathogenesis of Parkinson’s disease. Ann. NY Acad. Sci. 991, 189–198 (2003)

    Article  ADS  CAS  PubMed  Google Scholar 

  37. Petroske, E., Meredith, G. E., Callen, S., Totterdell, S. & Lau, Y. S. Mouse model of Parkinsonism: A comparison between subacute MPTP and chronic MPTP/probenecid treatment. Neuroscience 106, 589–601 (2001)

    Article  CAS  PubMed  Google Scholar 

  38. Wilson, C. J. & Callaway, J. C. Coupled oscillator model of the dopaminergic neuron of the substantia nigra. J. Neurophysiol. 83, 3084–3100 (2000)

    Article  CAS  PubMed  Google Scholar 

  39. Orrenius, S., Zhivotovsky, B. & Nicotera, P. Regulation of cell death: The calcium-apoptosis link. Nature Rev. Mol. Cell Biol. 4, 552–565 (2003)

    Article  CAS  Google Scholar 

  40. Kazuno, A. A. et al. Identification of mitochondrial DNA polymorphisms that alter mitochondrial matrix pH and intracellular calcium dynamics. PLoS Genet. 2, e128 (2006)

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Yamada, T., McGeer, P. L., Baimbridge, K. G. & McGeer, E. G. Relative sparing in Parkinson’s disease of substantia nigra dopamine neurons containing calbindin-D28K. Brain Res. 526, 303–307 (1990)

    Article  CAS  PubMed  Google Scholar 

  42. Ai, Y. et al. Intraputamenal infusion of GDNF in aged rhesus monkeys: Distribution and dopaminergic effects. J. Comp. Neurol. 461, 250–261 (2003)

    Article  CAS  PubMed  Google Scholar 

  43. Coleman, M. Axon degeneration mechanisms: Commonality amid diversity. Nature Rev. Neurosci. 6, 889–898 (2005)

    Article  CAS  Google Scholar 

  44. Kupsch, A. et al. Pretreatment with nimodipine prevents MPTP-induced neurotoxicity at the nigral, but not at the striatal level in mice. Neuroreport 6, 621–625 (1995)

    Article  CAS  PubMed  Google Scholar 

  45. Kupsch, A. et al. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurotoxicity in non-human primates is antagonized by pretreatment with nimodipine at the nigral, but not at the striatal level. Brain Res. 741, 185–196 (1996)

    Article  CAS  PubMed  Google Scholar 

  46. Grossman, E., Messerli, F. H., Oren, S., Nunez, B. & Garavaglia, G. E. Cardiovascular effects of isradipine in essential hypertension. Am. J. Cardiol. 68, 65–70 (1991)

    Article  CAS  PubMed  Google Scholar 

  47. Johnson, B. A., Devous, M. D., Ruiz, P. & Ait-Daoud, N. Treatment advances for cocaine-induced ischemic stroke: Focus on dihydropyridine-class calcium channel antagonists. Am. J. Psychiatry 158, 1191–1198 (2001)

    Article  CAS  PubMed  Google Scholar 

  48. Rodnitzky, R. L. Can calcium antagonists provide a neuroprotective effect in Parkinson’s disease? Drugs 57, 845–849 (1999)

    Article  CAS  PubMed  Google Scholar 

  49. Chan, C. S., Shigemoto, R., Mercer, J. N. & Surmeier, D. J. HCN2 and HCN1 channels govern the regularity of autonomous pacemaking and synaptic resetting in globus pallidus neurons. J. Neurosci. 24, 9921–9932 (2004)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Hows, M. E. et al. High-performance liquid chromatography/tandem mass spectrometry assay for the determination of 1-methyl-4-phenyl pyridinium (MPP+) in brain tissue homogenates. J. Neurosci. Methods 137, 221–226 (2004)

    Article  CAS  PubMed  Google Scholar 

  51. Platzer, J. et al. Congenital deafness and sinoatrial node dysfunction in mice lacking class D L-type Ca2+ channels. Cell 102, 89–97 (2000)

    Article  CAS  PubMed  Google Scholar 

  52. Nelson, E. L., Liang, C. L., Sinton, C. M. & German, D. C. Midbrain dopaminergic neurons in the mouse: Computer-assisted mapping. J. Comp. Neurol. 369, 361–371 (1996)

    Article  CAS  PubMed  Google Scholar 

  53. Paxinos, G. & Franklin, K. B. J. The Mouse Brain in Stereotaxic Coordinates (Elsevier Academic, San Diego, 2004)

    Google Scholar 

  54. Grace, A. A. & Bunney, B. S. The control of firing pattern in nigral dopamine neurons: Single spike firing. J. Neurosci. 4, 2866–2876 (1984)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Grace, A. A. & Onn, S. P. Morphology and electrophysiological properties of immunocytochemically identified rat dopamine neurons recorded in vitro. J. Neurosci. 9, 3463–3481 (1989)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Yung, W. H., Hausser, M. A. & Jack, J. J. Electrophysiology of dopaminergic and non-dopaminergic neurones of the guinea-pig substantia nigra pars compacta in vitro. J. Physiol. (Lond.) 436, 643–667 (1991)

    Article  CAS  Google Scholar 

  57. Maurice, N. et al. D2 dopamine receptor-mediated modulation of voltage-dependent Na+ channels reduces autonomous activity in striatal cholinergic interneurons. J. Neurosci. 24, 10289–10301 (2004)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Tkatch, T., Baranauskas, G. & Surmeier, D. J. Basal forebrain neurons adjacent to the globus pallidus co-express GABAergic and cholinergic marker mRNAs. Neuroreport 9, 1935–1939 (1998)

    Article  CAS  PubMed  Google Scholar 

  59. Song, W. J. et al. Somatodendritic depolarization-activated potassium currents in rat neostriatal cholinergic interneurons are predominantly of the A type and attributable to coexpression of Kv4.2 and Kv4.1 subunits. J. Neurosci. 18, 3124–3137 (1998)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Surmeier, D. J., Song, W. J. & Yan, Z. Coordinated expression of dopamine receptors in neostriatal medium spiny neurons. J. Neurosci. 16, 6579–6591 (1996)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Mandir, A. S. et al. Poly(ADP-ribose) polymerase activation mediates 1-methyl-4-phenyl-1, 2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism. Proc. Natl Acad. Sci. USA 96, 5774–5779 (1999)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  62. Meredith, G. E. & Kang, U. J. Behavioral models of Parkinson’s disease in rodents: A new look at an old problem. Mov. Disord. 21, 1595–1606 (2006)

    Article  PubMed  Google Scholar 

  63. Hines, M. L. & Carnevale, N. T. NEURON: A tool for neuroscientists. Neuroscientist 7, 123–135 (2001)

    Article  CAS  PubMed  Google Scholar 

  64. Migliore, M., Cook, E. P., Jaffe, D. B., Turner, D. A. & Johnston, D. Computer simulations of morphologically reconstructed CA3 hippocampal neurons. J. Neurophysiol. 73, 1157–1168 (1995)

    Article  CAS  PubMed  Google Scholar 

  65. Wang, J., Chen, S., Nolan, M. F. & Siegelbaum, S. A. Activity-dependent regulation of HCN pacemaker channels by cyclic AMP: Signaling through dynamic allosteric coupling. Neuron 36, 451–461 (2002)

    Article  CAS  PubMed  Google Scholar 

  66. Shen, W., Hamilton, S. E., Nathanson, N. M. & Surmeier, D. J. Cholinergic suppression of KCNQ channel currents enhances excitability of striatal medium spiny neurons. J. Neurosci. 25, 7449–7458 (2005)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by grants from the Picower Foundation and NIH NINDS to D.J.S. and G.E.M. We thank J. Held, D. Wokosin, P. Hockberger, E. Mugnaini, S. Ulrich, K. Saporito, Q. Ruan, J. Jackolin, F. Jodelka and M. Avram for help with this work.

Author information

Author notes

  1. Caroline Rick

    Present address: Present address: BCTU, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.,

Authors and Affiliations

  1. Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA,

    C. Savio Chan, Jaime N. Guzman, Ema Ilijic, Jeff N. Mercer, Caroline Rick, Tatiana Tkatch & D. James Surmeier

  2. Department of Cellular and Molecular Pharmacology, Chicago Medical School, Rosalind Franklin University of Medicine and Science, 3333 Green Bay Road, Chicago, Illinois 60064, USA,

    Gloria E. Meredith

Authors
  1. C. Savio Chan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jaime N. Guzman
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ema Ilijic
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jeff N. Mercer
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Caroline Rick
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Tatiana Tkatch
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Gloria E. Meredith
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. D. James Surmeier
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to D. James Surmeier.

Ethics declarations

Competing interests

Reprints and permissions information is available at www.nature.com/reprints. The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Figures S1-S7 with Legends. (PDF 4256 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Chan, C., Guzman, J., Ilijic, E. et al. ‘Rejuvenation’ protects neurons in mouse models of Parkinson’s disease. Nature 447, 1081–1086 (2007). https://doi.org/10.1038/nature05865

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature05865

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing