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.

  • Progress
  • Published:

Research in motion: the enigma of Parkinson's disease pathology spread

Nature Reviews Neuroscience volume 9, pages 741–745 (2008)Cite this article

Abstract

Neuropathological changes in Parkinson's disease progress slowly and spread according to a characteristic pattern. Recent papers have shed light on this progression of pathology by examining the fate of neurons grafted into the brains of patients with Parkinson's disease. Two of these studies demonstrate that grafted healthy neurons can gradually develop the same pathology as host neurons in the diseased brains. According to these studies, implanted neurons developed α-synuclein- and ubiquitin-positive Lewy bodies more than a decade after transplantation. We discuss the possible underlying mechanisms and their implications for how pathology spreads in Parkinson's 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: Lewy bodies develop in grafted neurons in Parkinson's disease.
Figure 2: Mechanisms that might explain why Lewy bodies form in grafted neurons.

Similar content being viewed by others

References

  1. Poewe, W. Non-motor symptoms in Parkinson's disease. Eur. J. Neurol. 15 (Suppl. 1), 14–20 (2008).

    Article  Google Scholar 

  2. Braak, H. et al. Staging of brain pathology related to sporadic Parkinson's disease. Neurobiol. Aging 24, 197–211 (2003).

    Article  Google Scholar 

  3. Ince, P. G., Clark, B., Holton, J. L., Revesz, T. & Wharton, S. in Greenfield's Neuropathology (eds Ellison, D. W., Louis, D. N. & Love, S.) 889–1030 (Arnold, London, 2008).

    Google Scholar 

  4. Kordower, J. H., Chu, Y., Hauser, R. A., Freeman, T. B. & Olanow, C. W. Lewy body-like pathology in long-term embryonic nigral transplants in Parkinson's disease. Nature Med. 14, 504–506 (2008).

    Article  CAS  Google Scholar 

  5. Li, J. Y. et al. Lewy bodies in grafted neurons in subjects with Parkinson's disease suggest host-to-graft disease propagation. Nature Med. 14, 501–503 (2008).

    Article  CAS  Google Scholar 

  6. Mendez, I. et al. Dopamine neurons implanted into people with Parkinson's disease survive without pathology for 14 years. Nature Med. 14, 507–509 (2008).

    Article  CAS  Google Scholar 

  7. Uryu, K. et al. Convergence of heat shock protein 90 with ubiquitin in filamentous α-synuclein inclusions of α-synucleinopathies. Am. J. Pathol. 168, 947–961 (2006).

    Article  CAS  Google Scholar 

  8. Uversky, V. N. Neuropathology, biochemistry, and biophysics of α-synuclein aggregation. J. Neurochem. 103, 17–37 (2007).

    CAS  PubMed  Google Scholar 

  9. Halliday, G. M. et al. α-synuclein redistributes to neuromelanin lipid in the substantia nigra early in Parkinson's disease. Brain 128, 2654–2664 (2005).

    Article  Google Scholar 

  10. Chu, Y. & Kordower, J. H. Age-associated increases of α-synuclein in monkeys and humans are associated with nigrostriatal dopamine depletion: is this the target for Parkinson's disease? Neurobiol. Dis. 25, 134–149 (2007).

    Article  CAS  Google Scholar 

  11. Greffard, S. et al. A stable proportion of Lewy body bearing neurons in the substantia nigra suggests a model in which the Lewy body causes neuronal death. Neurobiol. Aging 3 May 2008 (doi:10.1016/j.neurobiolaging.2008.03.015).

    Article  CAS  Google Scholar 

  12. Goldmann Gross, R., Siderowf, A. & Hurtig, H. I. Cognitive impairment in Parkinson's disease and dementia with lewy bodies: a spectrum of disease. Neurosignals 16, 24–34 (2008).

    Article  CAS  Google Scholar 

  13. McKeith, I. G. et al. Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium. Neurology 65, 1863–1872 (2005).

    Article  CAS  Google Scholar 

  14. Dickson, D. W. et al. Evidence that incidental Lewy body disease is pre-symptomatic Parkinson's disease. Acta Neuropathol. 115, 437–444 (2008).

    Article  Google Scholar 

  15. Farrer, M. et al. Comparison of kindreds with parkinsonism and α-synuclein genomic multiplications. Ann. Neurol. 55, 174–179 (2004).

    Article  CAS  Google Scholar 

  16. Fuchs, J. et al. Phenotypic variation in a large Swedish pedigree due to SNCA duplication and triplication. Neurology 68, 916–922 (2007).

    Article  CAS  Google Scholar 

  17. Goedert, M., Jakes, R. & Spillantini, M. G. Alpha-synuclein and the Lewy body. NeuroScience News 1, 2–7 (1998).

    Google Scholar 

  18. Wood-Kaczmar, A., Gandhi, S. & Wood, N. W. Understanding the molecular causes of Parkinson's disease. Trends Mol. Med. 12, 521–528 (2006).

    Article  CAS  Google Scholar 

  19. Schiesling, C., Kieper, N., Seidel, K. & Kruger, R. Review: Familial Parkinson's disease — genetics, clinical phenotype and neuropathology in relation to the common sporadic form of the disease. Neuropathol. Appl. Neurobiol. 34, 255–271 (2008).

    Article  CAS  Google Scholar 

  20. Kalaitzakis, M. E., Graeber, M. B., Gentleman, S. M. & Pearce, R. K. Controversies over the staging of α-synuclein pathology in Parkinson's disease. Acta Neuropathol. 116, 125–128 (2008).

    Article  Google Scholar 

  21. Braak, H. & Del Tredici, K. Invited Article: Nervous system pathology in sporadic Parkinson disease. Neurology 70, 1916–1925 (2008).

    Article  Google Scholar 

  22. Jellinger, K. A. A critical reappraisal of current staging of Lewy-related pathology in human brain. Acta Neuropathol. 116, 1–16 (2008).

    Article  CAS  Google Scholar 

  23. Li, J. Y. et al. Long-term surviving transplanted dopamine neurons exhibit α-synuclein accumulation and Lewy bodies. Mov. Disord. Soc. 12th Int. Congress Parkinson's Dis. Mov. Disord. LB13, 11–12 (2008).

    Google Scholar 

  24. Lobsiger, C. S. & Cleveland, D. W. Glial cells as intrinsic components of non-cell-autonomous neurodegenerative disease. Nature Neurosci. 10, 1355–1360 (2007).

    Article  CAS  Google Scholar 

  25. McGeer, P. L., Itagaki, S., Boyes, B. E. & McGeer, E. G. Reactive microglia are positive for HLA-DR in the substantia nigra of Parkinson's and Alzheimer's disease brains. Neurology 38, 1285–1291 (1988).

    Article  CAS  Google Scholar 

  26. Whitton, P. S. Inflammation as a causative factor in the aetiology of Parkinson's disease. Br. J. Pharmacol. 150, 963–976 (2007).

    Article  CAS  Google Scholar 

  27. Duan, W. M., Widner, H. & Brundin, P. Temporal pattern of host responses against intrastriatal grafts of syngeneic, allogeneic or xenogeneic embryonic neuronal tissue in rats. Exp. Brain Res. 104, 227–242 (1995).

    Article  CAS  Google Scholar 

  28. Griffin, W. S., Liu, L., Li, Y., Mrak, R. E. & Barger, S. W. Interleukin-1 mediates Alzheimer and Lewy body pathologies. J. Neuroinflammation 3, 5 (2006).

    Article  Google Scholar 

  29. Shavali, S., Combs, C. K. & Ebadi, M. Reactive macrophages increase oxidative stress and alpha-synuclein nitration during death of dopaminergic neuronal cells in co-culture: relevance to Parkinson's disease. Neurochem. Res. 31, 85–94 (2006).

    Article  CAS  Google Scholar 

  30. Jenner, P. Oxidative stress in Parkinson's disease. Ann. Neurol. 53 (Suppl. 3), S26–S36; discussion S36–S38 (2003).

    Article  CAS  Google Scholar 

  31. Lotharius, J. & Brundin, P. Pathogenesis of Parkinson's disease: dopamine, vesicles and α-synuclein. Nature Rev. Neurosci. 3, 932–942 (2002).

    Article  CAS  Google Scholar 

  32. Takahashi, M. et al. Oxidative stress-induced phosphorylation, degradation and aggregation of α-synuclein are linked to upregulated CK2 and cathepsin D. Eur. J. Neurosci. 26, 863–874 (2007).

    Article  Google Scholar 

  33. Vila, M. et al. α-synuclein up-regulation in substantia nigra dopaminergic neurons following administration of the parkinsonian toxin MPTP. J. Neurochem. 74, 721–729 (2000).

    Article  CAS  Google Scholar 

  34. Gopinath, G., Shetty, A. K. & Tandon, P. N. Ageing changes in the transplants of fetal substantia nigra grafted to striatum of adult rat. Neuroscience 40, 429–443 (1991).

    Article  CAS  Google Scholar 

  35. Shtilerman, M. D., Ding, T. T. & Lansbury, P. T. Jr. Molecular crowding accelerates fibrillization of α-synuclein: could an increase in the cytoplasmic protein concentration induce Parkinson's disease? Biochemistry 41, 3855–3860 (2002).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  37. Sonsalla, P. K., Albers, D. S. & Zeevalk, G. D. Role of glutamate in neurodegeneration of dopamine neurons in several animal models of parkinsonism. Amino Acids 14, 69–74 (1998).

    Article  CAS  Google Scholar 

  38. Rutherford, A., Garcia-Munoz, M., Dunnett, S. B. & Arbuthnott, G. W. Electrophysiological demonstration of host cortical inputs to striatal grafts. Neurosci. Lett. 83, 275–281 (1987).

    Article  CAS  Google Scholar 

  39. Doucet, G. et al. Host afferents into intrastriatal transplants of fetal ventral mesencephalon. Exp. Neurol. 106, 1–19 (1989).

    Article  CAS  Google Scholar 

  40. Fisher, L. J., Young, S. J., Tepper, J. M., Groves, P. M. & Gage, F. H. Electrophysiological characteristics of cells within mesencephalon suspension grafts. Neuroscience 40, 109–122 (1991).

    Article  CAS  Google Scholar 

  41. Siegel, G. J. & Chauhan, N. B. Neurotrophic factors in Alzheimer's and Parkinson's disease brain. Brain Res. Rev. 33, 199–227 (2000).

    Article  CAS  Google Scholar 

  42. Smith, M. P. & Cass, W. A. GDNF reduces oxidative stress in a 6-hydroxydopamine model of Parkinson's disease. Neurosci. Lett. 412, 259–263 (2007).

    Article  CAS  Google Scholar 

  43. Meyer-Luehmann, M. et al. Exogenous induction of cerebral β-amyloidogenesis is governed by agent and host. Science 313, 1781–1784 (2006).

    Article  CAS  Google Scholar 

  44. Braak, H., Rub, U., Gai, W. P. & Del Tredici, K. Idiopathic Parkinson's disease: possible routes by which vulnerable neuronal types may be subject to neuroinvasion by an unknown pathogen. J. Neural Transm. 110, 517–536 (2003).

    Article  CAS  Google Scholar 

  45. Hardy, J. Expression of normal sequence pathogenic proteins for neurodegenerative disease contributes to disease risk: 'permissive templating' as a general mechanism underlying neurodegeneration. Biochem. Soc. Trans. 33, 578–581 (2005).

    Article  CAS  Google Scholar 

  46. Mori, F. et al. α-synuclein pathology in the neostriatum in Parkinson's disease. Acta Neuropathol. 115, 453–459 (2008).

    Article  CAS  Google Scholar 

  47. Kordower, J. H. & Sortwell, C. E. Neuropathology of fetal nigra transplants for Parkinson's disease. Prog. Brain Res. 127, 333–344 (2000).

    Article  CAS  Google Scholar 

  48. Lee, H. J., Patel, S. & Lee, S. J. Intravesicular localization and exocytosis of α-synuclein and its aggregates. J. Neurosci. 25, 6016–6024 (2005).

    Article  CAS  Google Scholar 

  49. Mollenhauer, B. et al. Direct quantification of CSF α-synuclein by ELISA and first cross-sectional study in patients with neurodegeneration. Exp. Neurol. 14 Jun 2008 (doi:10.1016/j.expneurol.2008.06.004).

    Article  CAS  Google Scholar 

  50. Borghi, R. et al. Full length α-synuclein is present in cerebrospinal fluid from Parkinson's disease and normal subjects. Neurosci. Lett. 287, 65–67 (2000).

    Article  CAS  Google Scholar 

  51. El-Agnaf, O. M. et al. α-synuclein implicated in Parkinson's disease is present in extracellular biological fluids, including human plasma. FASEB J. 17, 1945–1947 (2003).

    Article  CAS  Google Scholar 

  52. Tokuda, T. et al. Decreased α-synuclein in cerebrospinal fluid of aged individuals and subjects with Parkinson's disease. Biochem. Biophys. Res. Commun. 349, 162–166 (2006).

    Article  CAS  Google Scholar 

  53. Lee, H. J. et al. Assembly-dependent endocytosis and clearance of extracellular α-synuclein. Int. J. Biochem. Cell Biol. 40, 1835–1849 (2008).

    Article  CAS  Google Scholar 

  54. Ahn, K. J., Paik, S. R., Chung, K. C. & Kim, J. Amino acid sequence motifs and mechanistic features of the membrane translocation of α-synuclein. J. Neurochem. 97, 265–279 (2006).

    Article  CAS  Google Scholar 

  55. Sung, J. Y. et al. Induction of neuronal cell death by Rab5A-dependent endocytosis of α-synuclein. J. Biol. Chem. 276, 27441–27448 (2001).

    Article  CAS  Google Scholar 

  56. Hagell, P. et al. Sequential bilateral transplantation in Parkinson's disease: effects of the second graft. Brain 122, 1121–1132 (1999).

    Article  Google Scholar 

Download references

Acknowledgements

This work was supported by grants from the Swedish Research Council, Swedish Parkinson Foundation, the Nordic Center of Excellence on Neurodegeneration and The Strong Research Environment of the Swedish Research Council (NeuroFortis). The Queen Square Brain Bank is supported by the Reta Lila Weston Institute of Neurological Studies, the Progressive Supranuclear Palsy (Europe) Association and BrainNet Europe. T.R. and J.L.H. are supported by grants from the Alzheimer's Research Trust and the Sarah Matheson Trust.

Author information

Author notes

  1. Patrik.Brundin@med.lu.se

Authors and Affiliations

  1. Department of Experimental Medical Science,Wallenberg Neuroscience Center, Patrik Brundin and Jia-Yi Li are at the Neuronal Survival Unit, Lund University, SE-221 84 Lund, Sweden.,

    Patrik Brundin & Jia-Yi Li

  2. Department of Molecular Neuroscience, Janice L. Holton and Tamas Revesz are at the Queen Square Brain Bank for Neurological Disorders, Institute of Neurology, University College London, London, WC1N 3BG, UK.,

    Janice L. Holton & Tamas Revesz

  3. and at the Division of Neurology, Department of Clinical Sciences, Olle Lindvall is at the Section of Restorative Neurology, Wallenberg Neuroscience Center, Lund University, SE-221 84 Lund, Sweden, Lund University Hospital, SE-221 85 Lund, Sweden.,

    Olle Lindvall

Authors
  1. Patrik Brundin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jia-Yi Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Janice L. Holton
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Olle Lindvall
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Tamas Revesz
    View author publications

    You can also search for this author in PubMed Google Scholar

Related links

Related links

DATABASES

OMIM

PD

FURTHER INFORMATION

Patrik Brundin's homepage

Rights and permissions

Reprints and permissions

About this article

Cite this article

Brundin, P., Li, JY., Holton, J. et al. Research in motion: the enigma of Parkinson's disease pathology spread. Nat Rev Neurosci 9, 741–745 (2008). https://doi.org/10.1038/nrn2477

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrn2477

This article is cited by

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