Skip to main content

Lack of functional relevance of isolated cell damage in transplants of Parkinson’s disease patients

Abstract

Postmortem analyses from clinical neural transplantation trials of several subjects with Parkinson’s disease revealed surviving grafted dopaminergic neurons after more than a decade. A subset of these subjects displayed isolated dopaminergic neurons within the grafts that contained Lewy body-like structures. In this review, we discuss why this isolated cell damage is unlikely to affect the overall graft function and how we can use these observations to help us to understand age-related neurodegeneration and refine our future cell replacement therapies.

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4

References

  1. Appel SH (2009) CD4+T cells mediate cytotoxicity in neurodegenerative diseases. J Clin Invest 119:13–15

    PubMed  CAS  Google Scholar 

  2. Astradsson A, Cooper O, Vinuela A, Isacson O (2008) Recent advances in cell-based therapy for Parkinson disease. Neurosurg Focus 24:E6

    PubMed  Article  Google Scholar 

  3. Astradsson A, Jenkins BG, Choi JK, Hallett PJ, Levesque MA, McDowell JS, Brownell AL, Spealman RD, Isacson O (2009) The blood–brain barrier is intact after levodopa-induced dyskinesias in parkinsonian primates—evidence from in vivo neuroimaging studies. Neurobiol Dis

  4. Brundin P, Li JY, Holton JL, Lindvall O, Revesz T (2008) Research in motion: the enigma of Parkinson’s disease pathology spread. Nat Rev Neurosci 9:741–745

    PubMed  Article  CAS  Google Scholar 

  5. Carlsson T, Carta M, Winkler C, Bjorklund A, Kirik D (2007) Serotonin neuron transplants exacerbate L-DOPA-induced dyskinesias in a rat model of Parkinson’s disease. J Neurosci 27:8011–8022

    PubMed  Article  CAS  Google Scholar 

  6. Carta M, Carlsson T, Kirik D, Bjorklund A (2007) Dopamine released from 5-HT terminals is the cause of L-DOPA-induced dyskinesia in parkinsonian rats. Brain 130:1819–1833

    PubMed  Article  Google Scholar 

  7. Chung CY, Seo H, Sonntag KC, Brooks A, Lin L, Isacson O (2005) Cell type-specific gene expression of midbrain dopaminergic neurons reveals molecules involved in their vulnerability and protection. Hum Mol Genet 14:1709–1725

    PubMed  Article  CAS  Google Scholar 

  8. Fahn S (2003) Description of Parkinson’s disease as a clinical syndrome. Ann N Y Acad Sci 991:1–14

    PubMed  CAS  Google Scholar 

  9. Freed CR, Greene PE, Breeze RE, Tsai WY, DuMouchel W, Kao R, Dillon S, Winfield H, Culver S, Trojanowski JQ, Eidelberg D, Fahn S (2001) Transplantation of embryonic dopamine neurons for severe Parkinson’s disease. N Engl J Med 344:710–719

    PubMed  Article  CAS  Google Scholar 

  10. Gao HM, Kotzbauer PT, Uryu K, Leight S, Trojanowski JQ, Lee VM (2008) Neuroinflammation and oxidation/nitration of alpha-synuclein linked to dopaminergic neurodegeneration. J Neurosci 28:7687–7698

    PubMed  Article  CAS  Google Scholar 

  11. Geny C, Naimi-Sadaoui S, Jeny R, Belkadi AM, Juliano SL, Peschanski M (1994) Long-term delayed vascularization of human neural transplants to the rat brain. J Neurosci 14:7553–7562

    PubMed  CAS  Google Scholar 

  12. Hauser RA, Freeman TB, Snow BJ, Nauert M, Gauger L, Kordower JH, Olanow CW (1999) Long-term evaluation of bilateral fetal nigral transplantation in Parkinson disease. Arch Neurol 56:179–187

    PubMed  Article  CAS  Google Scholar 

  13. Hedlund E, Pruszak J, Lardaro T, Ludwig W, Vinuela A, Kim KS, Isacson O (2008) Embryonic stem cell-derived Pitx3-enhanced green fluorescent protein midbrain dopamine neurons survive enrichment by fluorescence-activated cell sorting and function in an animal model of Parkinson’s disease. Stem Cells 26:1526–1536

    PubMed  Article  CAS  Google Scholar 

  14. Isacson O (2003) The production and use of cells as therapeutic agents in neurodegenerative diseases. Lancet Neurol 2:417–424

    PubMed  Article  CAS  Google Scholar 

  15. Isacson O, Bjorklund LM, Schumacher JM (2003) Towards full restoration of synaptic and terminal function of the dopaminergic system in Parkinson’s disease from regeneration and neuronal replacement by stem cells. Ann Neurol 53:135–148

    Article  CAS  Google Scholar 

  16. Isacson O, Kordower JH (2008) Future of cell and gene therapies for Parkinson’s disease. Ann Neurol 64(Suppl 2):S122–S138

    PubMed  CAS  Google Scholar 

  17. Kanaan NM, Kordower JH, Collier TJ (2007) Age-related accumulation of Marinesco bodies and lipofuscin in rhesus monkey midbrain dopamine neurons: relevance to selective neuronal vulnerability. J Comp Neurol 502:683–700

    PubMed  Article  Google Scholar 

  18. Kanaan NM, Kordower JH, Collier TJ (2008) Age-related changes in dopamine transporters and accumulation of 3-nitrotyrosine in rhesus monkey midbrain dopamine neurons: relevance in selective neuronal vulnerability to degeneration. Eur J Neurosci 27:3205–3215

    PubMed  Article  CAS  Google Scholar 

  19. Koprich JB, Reske-Nielsen C, Mithal P, Isacson O (2008) Neuroinflammation mediated by IL-1beta increases susceptibility of dopamine neurons to degeneration in an animal model of Parkinson’s disease. J Neuroinflammation 5:8

    PubMed  Article  CAS  Google Scholar 

  20. Kordower J, Freeman T, Chen E, Mufson E, Sanberg P, Hauser R, Snow B, Olanow C (1998) Fetal nigral grafts survive and mediate clinical benefit in a patient with Parkinson’s disease. Mov Disord 13:383–393

    PubMed  Article  CAS  Google Scholar 

  21. Kordower JH, Chu Y, Hauser RA, Freeman TB, Olanow CW (2008) Lewy body-like pathology in long-term embryonic nigral transplants in Parkinson’s disease. Nature Med 14:504–506

    PubMed  Article  CAS  Google Scholar 

  22. Kordower JH, Chu Y, Hauser RA, Olanow CW, Freeman TB (2008) Transplanted dopaminergic neurons develop PD pathologic changes: a second case report. Mov Disord 23:2303–2306

    PubMed  Article  Google Scholar 

  23. Kordower JH, Freeman TB, Snow BJ, Vingerhoets FJG, Mufson EJ, Sanberg PR, Hauser RA, Smith DA, Nauert M, Perl DP, Olanow CW (1995) Neuropathological evidence of graft survival and striatal reinnervation after the transplantation of fetal mesencephalic tissue in a patient with Parkinson’s disease. N Engl J Med 332:1118–1124

    PubMed  Article  CAS  Google Scholar 

  24. Krack P, Batir A, Van Blercom N, Chabardes S, Fraix V, Ardouin C, Koudsie A, Limousin PD, Benazzouz A, LeBas JF, Benabid AL, Pollak P (2003) Five-year follow-up of bilateral stimulation of the subthalamic nucleus in advanced Parkinson’s disease. N Engl J Med 349:1925–1934

    PubMed  Article  CAS  Google Scholar 

  25. Leigh K, Elisevich K, Rogers KA (1994) Vascularisation and microvascular permeability in solid versus cell-suspension embryonic neural grafts. J Neurosurg 81:272–283

    PubMed  Article  CAS  Google Scholar 

  26. Li JY, Englund E, Holton JL, Soulet D, Hagell P, Lees AJ, Lashley T, Quinn NP, Rehncrona S, Bjorklund A, Widner H, Revesz T, Lindvall O, Brundin P (2008) Lewy bodies in grafted neurons in subjects with Parkinson’s disease suggest host-to-graft disease propagation. Nature Med 14:501–503

    PubMed  Article  CAS  Google Scholar 

  27. Limousin P, Krack P, Pollak P, Benazzouz A, Ardouin C, Hoffmann D, Benabid AL (1998) Electrical stimulation of the subthalamic nucleus in advanced Parkinson’s disease. N Engl J Med 339:1105–1111

    PubMed  Article  CAS  Google Scholar 

  28. Limousin P, Pollak P, Benazzouz A, Hoffmann D, Le Bas JF, Broussolle E, Perret JE, Benabid AL (1995) Effect of parkinsonian signs and symptoms of bilateral subthalamic nucleus stimulation. Lancet 345:91–95

    PubMed  Article  CAS  Google Scholar 

  29. Lindvall O, Brundin P, Widner H, Rehncrona S, Gustavii B, Frackowiak R, Leenders KL, Sawle G, Rothwell JC, Marsden CD et al (1990) Grafts of fetal dopamine neurons survive and improve motor function in Parkinson’s disease. Science 247:574–577

    PubMed  Article  CAS  Google Scholar 

  30. Lindvall O, Sawle G, Widner H, Rothwell JC, Bjorklund A, Brooks D, Brundin P, Frackowiak RS, Marsden CD, Odin P, Rehncrona S (1994) Evidence for long-term survival and function of dopaminergic grafts in progressive Parkinson’s disease. Ann Neurol 2:172–180

    Article  Google Scholar 

  31. Marsden CD (1982) Basal ganglia disease. Lancet 114:1–1147

    Google Scholar 

  32. Mendez I, Dagher A, Hong M, Gaudet P, Weerasinghe S, McAlister V, King D, Desrosiers J, Darvesh S, Acorn T, Robertson H (2002) Simultaneous intrastriatal and intranigral fetal dopaminergic grafts in patients with Parkinson disease: a pilot study. Report of three cases. J Neurosurg 96:589–596

    PubMed  Article  Google Scholar 

  33. Mendez I, Sanchez-Pernaute R, Cooper O, Vinuela A, Ferrari D, Bjorklund L, Dagher A, Isacson O (2005) Cell type analysis of functional fetal dopamine cell suspension transplants in the striatum and substantia nigra of patients with Parkinson’s disease. Brain 128:1498–1510

    PubMed  Article  Google Scholar 

  34. Mendez I, Vinuela A, Astradsson A, Mukhida K, Hallett P, Robertson H, Tierney T, Holness R, Dagher A, Trojanowski JQ, Isacson O (2008) Dopamine neurons implanted into people with Parkinson’s disease survive without pathology for 14 years. Nature Med 14:507–509

    PubMed  Article  CAS  Google Scholar 

  35. Meredith GE, Totterdell S, Potashkin JA, Surmeier DJ (2008) Modeling PD pathogenesis in mice: advantages of a chronic MPTP protocol. Parkinsonism Relat Disord 14(Suppl 2):S112–S115

    PubMed  Article  Google Scholar 

  36. Nagatsu T, Mogi M, Ichinose H, Togari A (2000) Changes in cytokines and neurotrophins in Parkinson’s disease. J Neural Transm 27(Suppl):7–290

    Google Scholar 

  37. Olanow CW, Goetz CG, Kordower JH, Stoessl AJ, Sossi V, Brin MF, Shannon KM, Nauert GM, Perl DP, Godbold J, Freeman TB (2003) A double-blind controlled trial of bilateral fetal nigral transplantation in Parkinson’s disease. Ann Neurol 54:403–414

    PubMed  Article  Google Scholar 

  38. Ostergaard K, Aa Sunde N (2006) Evolution of Parkinson’s disease during 4 years of bilateral deep brain stimulation of the subthalamic nucleus. Mov Disord 21:624–631

    PubMed  Article  Google Scholar 

  39. Piccini P, Brooks DJ, Bjorklund A, Gunn RN, Grasby PM, Rimoldi O, Brundin P, Hagell P, Rehncrona S, Widner H, Lindvall O (1999) Dopamine release from nigral transplants visualized in vivo in a Parkinson’s patient. Nature Neurosci 2:1137–1140

    PubMed  Article  CAS  Google Scholar 

  40. Piccini P, Lindvall O, Bjorklund A, Brundin P, Hagell P, Ceravolo R, Oertel W, Quinn N, Samuel M, Rehncrona S, Widner H, Brooks DJ (2000) Delayed recovery of movement-related cortical function in Parkinson’s disease after striatal dopaminergic grafts. Ann Neurol 48:689–695

    PubMed  Article  CAS  Google Scholar 

  41. Redmond DE Jr, Vinuela A, Kordower JH, Isacson O (2008) Influence of cell preparation and target location on the behavioral recovery after striatal transplantation of fetal dopaminergic neurons in a primate model of Parkinson’s disease. Neurobiol Dis 29:103–116

    PubMed  Article  CAS  Google Scholar 

  42. Rodriguez-Oroz MC, Obeso JA, Lang AE, Houeto JL, Pollak P, Rehncrona S, Kulisevsky J, Albanese A, Volkmann J, Hariz MI, Quinn NP, Speelman JD, Guridi J, Zamarbide I, Gironell A, Molet J, Pascual-Sedano B, Pidoux B, Bonnet AM, Agid Y, Xie J, Benabid AL, Lozano AM, Saint-Cyr J, Romito L, Contarino MF, Scerrati M, Fraix V, Van Blercom N (2005) Bilateral deep brain stimulation in Parkinson’s disease: a multicentre study with 4 years follow-up. Brain 128:2240–2249

    PubMed  Article  CAS  Google Scholar 

  43. Siegfried J, Lippitz B (1994) Bilateral chronic electrostimulation of ventroposterolateral pallidum: a new therapeutic approach for alleviating all parkinsonian symptoms. Neurosurgery 35:1126–1129 discussion 1129–1130

    PubMed  Article  CAS  Google Scholar 

  44. Spencer DD, Robbins RJ, Naftolin F, Marek KL, Vollmer T, Leranth C, Roth RH, Price LH, Gjedde A, Bunney BS et al (1992) Unilateral transplantation of human fetal mesencephalic tissue into the caudate nucleus of patients with Parkinson’s disease. N Engl J Med 327:1541–1548

    PubMed  CAS  Google Scholar 

  45. Villoslada P, Moreno B, Melero I, Pablos JL, Martino G, Uccelli A, Montalban X, Avila J, Rivest S, Acarin L, Appel S, Khoury SJ, McGeer P, Ferrer I, Delgado M, Obeso J, Schwartz M (2008) Immunotherapy for neurological diseases. Clin Immunol 128:294–305

    PubMed  Article  CAS  Google Scholar 

  46. Voon V, Krack P, Lang AE, Lozano AM, Dujardin K, Schupbach M, D’Ambrosia J, Thobois S, Tamma F, Herzog J, Speelman JD, Samanta J, Kubu C, Rossignol H, Poon YY, Saint-Cyr JA, Ardouin C, Moro E (2008) A multicentre study on suicide outcomes following subthalamic stimulation for Parkinson’s disease. Brain 131:2720–2728

    PubMed  Article  Google Scholar 

  47. Wernig M, Zhao JP, Pruszak J, Hedlund E, Fu D, Soldner F, Broccoli V, Constantine-Paton M, Isacson O, Jaenisch R (2008) Neurons derived from reprogrammed fibroblasts functionally integrate into the fetal brain and improve symptoms of rats with Parkinson’s disease. Proc Natl Acad Sci USA 105:5856–5861

    PubMed  Article  CAS  Google Scholar 

  48. Widner H, Tetrud J, Rehncrona S, Snow B, Brundin P, Gustavii B, Bjorklund A, Lindvall O, Langston JW (1992) Bilateral fetal mesencephalic grafting in two patients with parkinsonism induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). N Engl J Med 327:1556–1563

    PubMed  CAS  Article  Google Scholar 

Download references

Conflict of interest statement

The authors declare no conflict of interest.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Ole Isacson.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Cooper, O., Astradsson, A., Hallett, P. et al. Lack of functional relevance of isolated cell damage in transplants of Parkinson’s disease patients. J Neurol 256, 310–316 (2009). https://doi.org/10.1007/s00415-009-5242-z

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00415-009-5242-z

Keywords

  • Cell transplantation
  • Lewy body
  • Therapy
  • Dopaminergic