Necessary methodological and stem cell advances for restoration of the dopaminergic system in Parkinson's disease patients

doi:10.1017/CBO9780511544873.025

24 - Necessary methodological and stem cell advances for restoration of the dopaminergic system in Parkinson's disease patients

from Part III - Therapeutic approaches in neurodegeneration

Published online by Cambridge University Press: 04 August 2010

Anthony E. Lang and

Lars M. Bjorklund and

Rosario Sanchez-Pernaute

Show author details

M. Flint Beal: Affiliation:
Cornell University, New York
Anthony E. Lang: Affiliation:
University of Toronto
Albert C. Ludolph: Affiliation:
Universität Ulm, Germany
Ole Isacson: Affiliation:
Udall Parkinson's Disease Research Center of Excellence, Belmont, MA, USA
Kwang-Soo Kim: Affiliation:
Udall Parkinson's Disease Research Center of Excellence, Belmont, MA, USA
Ivar Mendez: Affiliation:
Division of Neurosurgery, Dalhousie University, Halifax, NS, Canada
Craig van Horne: Affiliation:
Udall Parkinson's Disease Research Center of Excellence, Belmont, MA, USA
Lars M. Bjorklund: Affiliation:
Udall Parkinson's Disease Research Center of Excellence, Belmont, MA, USA
Rosario Sanchez-Pernaute: Affiliation:
Udall Parkinson's Disease Research Center of Excellence, Belmont, MA, USA

Book contents

Get access

Summary

Introduction

New therapeutic non-pharmacological methodology involves cell and synaptic renewal or replacement in the living brain to restore function of neuronal systems, including the dopaminergic (DA) system in Parkinson's disease. Understanding the cell biological principles for generating functional DA neurons in lieu of the diseased can provide many new avenues for better treatment of patients with PD. Recent laboratory work has focused on using stem cells as a starting point for exogenous or endogenous derivation of the optimal DA cells for repair (Fig. 24.1). Using fetal DA cell therapy in PD patients (Piccini et al., 1999, 2000; Freed et al., 2001; Isacson et al., 2001; Mendez et al., 2002a) and stem cell-derived DA neurons in animal models (Bjorklund et al., 2002; Kim et al., 2002), it has been demonstrated that functional motor deficits associated with PD can be reduced after application of this new technology. Evidence shows that the underlying disease process does not destroy the transplanted fetal DA cells, although the patient's original DA system degeneration progresses (Piccini et al., 1999, 2000). The optimal DA cell regeneration system would reconstitute a normal network capable of restoring feedback-controlled release of DA in the nigro-striatal system (Bjorklund & Isacson, 2002). The success of cell therapy for neurological diseases is limited by access to preparation and development of highly specialized dopaminergic neurons found in the A9 and A10 region of the substantia nigra (SN) in the ventral mesencephalon, as well as technical and surgical steps associated with transplantation.

Type: Chapter
Information: Neurodegenerative Diseases
Neurobiology, Pathogenesis and Therapeutics
, pp. 363 - 380

DOI: https://doi.org/10.1017/CBO9780511544873.025 [Opens in a new window]

Publisher: Cambridge University Press

Print publication year: 2005

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

Book purchase

Temporarily unavailable

References

Abrous, N., Guy, J., Vigny, A., Calas, A., LeMoal, M. & Herman, J.- P. (1988). Development of intracerebral dopaminergic grafts: A combined immunohistochemical and autoradiographic study of its time course and environmental influences. J. Comp. Neurol., 273, 26–41CrossRef Google Scholar PubMed

Akerud, P., Canals, J. M., Snyder, E. Y. & Arenas, E. (2001). Neuroprotection through delivery of glial cell line-derived neurotrophic factor by neural stem cells in a mouse model of Parkinson's disease. J. Neurosci., 21, 8108–18CrossRef Google Scholar

Alvarez-Buylla, A. & Garcia-Verdugo, J. M. (2002). Neurogenesis in adult subventricular zone. J. Neurosci., 22, 629–34CrossRef Google Scholar PubMed

Backlund, E., Granberg, P. & Hamberger, B. (1985). Transplantation of adrenal medullary tissue to striatum in parkinsonism. J. Neurosurg., 62, 169–73CrossRef Google Scholar PubMed

Benraiss, A., Lerner, K., Chmielnicki, E.et al. (2000). Adenoviral transduction of the ventricular wall with a BDNF expression vector induces neuronal recruitment from endogenous progenitor cells in the adult forebrain. Mol. Ther., 1, S35–6Google Scholar

Bjorklund, A., Schmidt, R. H. & Stenevi, U. (1980). Functional reinnervation of the neostriatum in the adult rat by use of intraparenchymal grafting of dissociated cell suspensions from the substantia nigra. Cell Tissue Res., 212, 39–45CrossRef Google Scholar PubMed

Bjorklund, L. M. & Isacson, O. (2002). Regulation of dopamine cell type and transmitter function in fetal and stem cell transplantation for Parkinson's disease. Prog. Brain Res., 138, 411–20CrossRef Google Scholar PubMed

Bjorklund, L. M., Sánchez-Pernaute, R., Chung, S.et al. (2002). Embryonic stem cells develop into functional dopaminergic neurons after transplantation in a Parkinson rat model. Proc. Natl Acad. Sci., USA, 99, 2344–9CrossRef Google Scholar

Blanchard, V., Raisman-Vozari, R., Vyas, S.et al. (1994). Differential expression of tyrosine hydroxylase and membrane dopamine transporter genes in subpopulations of dopaminergic neurons of the rat mesencephalon. Brain Res. Mol. Brain Res., 22, 29–38CrossRef Google Scholar PubMed

Brownell, A. L., Livni, E., Galpern, W. & Isacson, O. (1998). In vivo PET imaging in rat of dopamine terminals reveals functional neural transplants. Ann. Neurol., 43, 387–90CrossRef Google Scholar PubMed

Brundin, P. & Bjorklund, A. (1998). Survival of expanded dopaminergic precursors is critical for clinical trials. Nat. Neurosci., 1, 537CrossRef Google Scholar PubMed

Brundin, P., Isacson, O. & Björklund, A. (1985). Monitoring of cell viability in suspensions of embryonic CNS tissue and its use as a criterion for intracerebral graft survival. Brain Res., 331, 251–9CrossRef Google Scholar PubMed

Brundin, P., Pogarell, O., Hagell, P.et al. (2000). Bilateral caudate and putamen grafts of embryonic mesencephalic tissue treated with lazaroids in Parkinson's disease. Brain, 123 (7), 1380–90CrossRef Google Scholar PubMed

Burns, L. H., Pakzaban, P., Deacon, T. W.et al. (1995). Selective putaminal excitotoxic lesions in non-human primates model the movement disorder of Huntington disease. Neuroscience, 64, 1007–17CrossRef Google Scholar PubMed

Castillo, S. O., Baffi, J. S., Palkovits, M.et al. (1998). Dopamine biosynthesis is selectively abolished in substantia nigra/ventral tegmental area but not in hypothalamic neurons in mice with targeted disruption of the Nurr1 gene. Mol. Cell Neurosci., 11, 36–46CrossRef Google Scholar

Check, E. (2002). Parkinson's patients show positive response to implants. Nature, 416, 666CrossRef Google Scholar PubMed

Chung, S., Sonntag, K. C., Andersson, T.et al. (2002). Genetic engineering of mouse embryonic stem cells by Nurr1 enhances differentiation and maturation into dopaminergic neurons. Eur. J. Neurosci., 16, 1829–38CrossRef Google Scholar PubMed

Ciliax, B. J., Drash, G. W., Staley, J. K.et al. (1999). Immunocytochemical localization of the dopamine transporter in human brain. J. Comp. Neurol., 409, 38–563.0.CO;2-1>CrossRef Google Scholar PubMed

Clarke, D. J., Brundin, P., Strecker, R. E., Nilsson, O. G., Bjorklund, A. & Lindvall, O. (1988). Human fetal dopamine neurons grafted in a rat model of Parkinson's disease: ultrastructural evidence for synapse formation using tyrosine hydroxylase immunocytochemistry. Exp. Brain Res., 73, 115–26CrossRef Google Scholar

Collier, T., Redmond, D. J., Roth, R., Elsworth, J., Taylor, J. & Sladek, J. J. (1997). Metabolic energy capacity of dopaminergic grafts and the implanted striatum in parkinsonian nonhuman primates as visualized with cytochrome oxidase histochemistry. Cell Transpl., 6, 135–40CrossRef Google Scholar PubMed

Costantini, L. C., Lin, L. & Isacson, O. (1997). Medial fetal ventral mesencephalon: a preferred source for dopamine neuron grafts. Neuroreport, 8, 2253–7CrossRef Google Scholar PubMed

Costantini, L. C. & Snyder-Keller, A. (1997). Co-transplantation of fetal lateral ganglionic eminence and ventral mesencephalon can augment function and development of intrastriatal transplants. Exp. Neurol., 145, 214–27CrossRef Google Scholar PubMed

Craig, C. G., Tropepe, V., Morshead, C. M., Reynolds, B. A., Weiss, S. & Kooy, D. (1996). In vivo growth factor expansion of endogenous subependymal neural precursor cell population in the adult mouse brain. J. Neurosci., 16, 2649–58CrossRef Google Scholar PubMed

Dahlstrom, A. & Fuxe, K. (1964). Localization of monoamines in the lower brain stem. Experientia, 20, 398–9CrossRef Google Scholar PubMed

Damier, P., Hirsch, E. C., Agid, Y. & Graybiel, A. M. (1999). The substantia nigra of the human brain. I. Nigrosomes and the nigral matrix, a compartmental organization based on calbindin D(28K) immunohistochemistry. Brain, 122, 1421–36CrossRef Google Scholar

Danielian, P. S. & McMahon, A. P. (1996). Engrailed-1 as a target of the Wnt-1 signalling pathway in vertebrate midbrain development. Nature, 383, 332–4CrossRef Google Scholar PubMed

Deacon, T., Dinsmore, J., Costantini, L., Ratliff, J. & Isacson, O. (1998). Blastula-stage stem cells differentiate into dopaminergic and serotonergic neurons after transplantation. Exp. Neurol., 149, 28–41CrossRef Google Scholar PubMed

Defer, G. L., Geny, C., Ricolfi, F.et al. (1996). Long-term outcome of unilaterally transplanted parkinsonian patients. I. Clinical approach. Brain, 119, 41–50CrossRef Google Scholar PubMed

Doucet, G., Murata, Y., Brundin, P.et al. (1989). Host afferents into intrastriatal transplants of fetal ventral mesencephalon. Exp Neurol., 106, 1–19CrossRef Google Scholar PubMed

Dunnett, S. B., Bunch, S. T., Gage, F. H. & Bjorklund, A. (1984). Dopamine-rich transplants in rats with 6-OHDA lesions of the ventral tegmental area. 1. Effects on spontaneous and drug-induced locomotor activity. Behav. Brain Res., 13, 71–82CrossRef Google Scholar PubMed

Eberhardt, O., Coelin, R. V., Kugler, S.et al. (2002). Protection by synergistic effects of adenovirus-mediated X-linked chromosome-linked inhibitor of apoptosis and glial-derived neurotrophic factor gene transfer in the 1-methyl-4-pheyl-1,2,3,6-tetrahydropyridine model of Parkinson's disease. J. Neurosci., 20, 9126–34CrossRef Google Scholar

Falkenburger, B. H., Barstow, K. L. & Mintz, I. M. (2001). Dendrodendritic inhibition through reversal of dopamine transport. Science, 293, 2465–70CrossRef Google Scholar PubMed

Fallon, J., Reid, S., Kinyamu, R.et al. (2000). In vivo induction of massive proliferation, directed migration, and differentiation of neural cells in the adult mammalian brain. Proc. Natl Acad. Sci., USA, 97, 14686–91CrossRef Google Scholar PubMed

Flax, J. D., Aurora, S., Yang, C.et al. (1998). Engraftable human neural stem cells respond to developmental cues, replace neurons, and express foreign genes. Nat. Biotechnol., 16, 1033–9Google Scholar PubMed

Freed, C. R., Breeze, R. E., Rosenberg, N. L.et al. (1990). Transplantation of human fetal dopamine cells for Parkinson's disease. Results at 1 year. Arch. Neurol., 47, 505–12CrossRef Google Scholar PubMed

Freed, C. R., Breeze, R. E., Rosenberg, N. L.et al. (1992). Survival of implanted fetal dopamine cells and neurologic improvement 12 to 46 months after transplantation for Parkinson's disease. N. Engl. J. Med., 327, 1549–55CrossRef Google Scholar PubMed

Freed, C. R., Greene, P. E., Breeze, R. E.et al. (2001). Transplantation of embryonic dopamine neurons for severe Parkinson's disease. N. Engl. J. Med., 344, 710–19CrossRef Google Scholar PubMed

Freeman, A. S., Meltzer, L. T. & Bunney, B. S. (1985). Firing properties of substantia nigra dopaminergic neurons in freely moving rats. Life Sci., 36, 1983–94CrossRef Google Scholar PubMed

Freeman, T. B., Olanow, C. W., Hauser, R. A.et al. (1995a). Bilateral fetal nigral transplantation into the postcommissural putamen in Parkinson's disease. Ann. Neurol., 38, 379–88CrossRef Google Scholar

Frim, D. M., Uhler, T. A., Galpern, W. R., Beal, M. F., Breakefield, X. O. & Isacson, O. (1994). Biologically delivered BDNF increases dopaminergic neuronal survival in a rat model of Parkinson's disease. Proc. Natl Acad. Sci., USA, 91, 5104–8CrossRef Google Scholar

Galpern, W. R., Burns, L. H., Deacon, T. W., Dinsmore, J. & Isacson, O. (1996). Xenotransplantation of porcine fetal ventral mesencephalon in a rat model of Parkinson's disease: functional recovery and graft morphology. Exp. Neurol., 140, 1–13CrossRef Google Scholar

Gaudin, D., Rioux, L. & Bedard, P. (1990). Fetal dopamine neuron transplants prevent behavioral supersensitivity induced by repeated administration of L-Dopa in the rat. Brain Res., 506, 166–8CrossRef Google Scholar PubMed

Gerfen, C., Keefe, K. & Steiner, H. (1998). Dopamine-mediated gene regulation in the striatum. Adv. Pharmacol., 42, 670–3CrossRef Google Scholar PubMed

Gerfen, C. R., Herkenham, M. & Thibault, J. (1987). The neostriatal mosaic: II. Patch- and matrix-directed mesostriatal dopaminergic and non-dopaminergic systems. J. Neurosci., 7, 3915–34CrossRef Google Scholar PubMed

German, D. C., Manaye, K. F., Sonsalla, P. K. & Brooks, B. A. (1992). Midbrain dopaminergic cell loss in Parkinson's disease and MPTP-induced parkinsonism: sparing of calbindin-D28k-containing cells. Ann. NY Acad. Sci., 648, 42–62CrossRef Google Scholar PubMed

Gibb, W. R. (1992). Melanin, tyrosine hydroxylase, calbindin and substance P in the human midbrain and substantia nigra in relation to nigrostriatal projections and differential neuronal susceptibility in Parkinson's disease. Brain Res., 581, 283–91CrossRef Google Scholar PubMed

Grace, A. A. (1991). Phasic versus tonic dopamine release and the modulation of dopamine system responsivity: a hypothesis for the etiology of schizophrenia. Neuroscience, 41, 1–24CrossRef Google Scholar PubMed

Granholm, A., Mott, J., Bowenkamp, K.et al. (1997). Glial cell line-derived neurotrophic factor improves survival of ventral mesencephalic grafts to the 6-hydroxydopamine lesioned striatum. Exp. Brain Res., 116, 29–38CrossRef Google Scholar PubMed

Graybiel, A. M., Hirsch, E. & Agid, Y. (1990). The nigrostriatal system in Parkinson's disease. In Advances in Neurology, ed. M. B. Streifler, A. D. Korczyn, E. Melamed & M. B. H. Youdim, pp. 17–29. New York: Raven Press

Haber, S. N., Ryoo, H., Cox, C. & Lu, W. (1995). Subsets of midbrain dopaminergic neurons in monkeys are distinguished by different levels of mRNA for the dopamine transporter: comparison with the mRNA for the D2 receptor, tyrosine hydroxylase and calbindin immunoreactivity. J. Comp. Neurol., 362, 400–10CrossRef Google Scholar PubMed

Hagell, P., Schrag, A., Piccini, P.et al. (1999). Sequential bilateral transplantation in Parkinson's disease: effects of the second graft. Brain, 122 (6), 1121–32CrossRef Google Scholar PubMed

Hagell, P., Piccini, P., Bjorklund, A.et al. (2002). Dyskinesias following neural transplantation in Parkinson's disease. Nat. Neurosc., 5, 627–8CrossRef Google Scholar PubMed

Hantraye, P., Riche, D., Maziere, M. & Isacson, O. (1990). A primate model of Huntington's disease: behavioral and anatomical studies of unilateral excitotoxic lesions of the caudate-putamen in the baboon. Exp. Neurol., 108, 91–104CrossRef Google Scholar PubMed

Hantraye, P. (1992). Intrastriatal transplantation of cross-species fetal striatal cells reduces abnormal movements in a primate model of Huntington disease. Proc. Natl Acad. Sci., USA, 89, 4187–91CrossRef Google Scholar

Haque, N. S., LeBlanc, C. J. & Isacson, O. (1997). Differential dissection of the rat E16 ventral mesencephalon and survival and reinnervation of the 6-OHDA-lesioned striatum by a subset of aldehyde dehydrogenase-positive TH neurons. Cell Transpl., 6, 239–48CrossRef Google Scholar PubMed

Hauser, R. A., Freeman, T. B., Snow, B. J.et al. (1999). Long-term evaluation of bilateral fetal nigral transplantation in Parkinson disease. Arch. Neurol., 56, 179–87CrossRef Google Scholar PubMed

Hemmati-Brivanlou, A. & Melton, D. (1997). Vertebrate embryonic cells will become nerve cells unless told otherwise. Cell, 88, 13–17CrossRef Google Scholar PubMed

Henderson, B. T., Clough, C. G., Hughes, R. C., Hitchcock, E. R. & Kenny, B. G. (1991). Implantation of human fetal ventral mesencephalon to the right caudate nucleus in advanced Parkinson's disease. Arch. Neurol., 48, 822–7CrossRef Google Scholar PubMed

Hernit-Grant, C. S. & Macklis, J. D. (1996). Embryonic neurons transplanted to regions of targeted photolytic cell death in adult mouse somatosensory cortex re-form specific callosal projections. Exp. Neurol., 139, 131–42CrossRef Google Scholar PubMed

Iacopino, A. M. & Christakos, S. (1990). Specific reduction of calcium-binding protein (28-kilodalton calbindin-D) gene expression in aging and neurodegenerative diseases. Proc. Natl Acad. Sci., USA, 87, 4078–82CrossRef Google Scholar PubMed

Isacson, O. & Deacon, T. W. (1996). Specific axon guidance factors persist in the mature rat brain: evidence from fetal neuronal xenografts. Neuroscience, 75, 827–37CrossRef Google Scholar

Isacson, O. & Deacon, T. W. (1997). Neural transplantation studies reveal the brain's capacity for continuous reconstruction. Trends in Neurosci., 20, 477–82CrossRef Google Scholar PubMed

Isacson, O., Deacon, T. W., Pakzaban, P., Galpern, W. R., Dinsmore, J. & Burns, L. H. (1995). Transplanted xenogeneic neural cells in neurodegenerative disease models exhibit remarkable axonal target specificity and distinct growth patterns of glial and axonal fibres. Nat. Med., 1, 1189–94CrossRef Google Scholar

Isacson, O., Bjorklund, L. & Pernaute, R. S. (2001). Parkinson's disease: interpretations of transplantation study are erroneous. Nat. Neurosci., 4, 553CrossRef Google Scholar PubMed

Ito, H., Goto, S., Sakamoto, S. & Hirano, A. (1992). Calbindin-D28k in the basal ganglia of patients with parkinsonism. Ann. Neurol., 32, 543–50CrossRef Google Scholar PubMed

Jacques, D. B., Kopyov, O. V., Eagle, K. S., Carter, T. & Lieberman, A. (1999). Outcomes and complications of fetal tissue transplantation in Parkinson's disease. Stereotact. Funct. Neurosurg., 72, 219–24CrossRef Google Scholar PubMed

Janec, E. & Burke, R. E. (1993). Naturally occuring cell death during postnatal development of the substantia nigra pars compacta of rat. Mol. Cell Neurosci., 4, 30–5CrossRef Google Scholar

Johansson, M., Friedemann, M., Hoffer, B. & Stromberg, I. (1995). Effects of glial cell line-derived neurotrophic factor on developing and mature ventral mesencephalic grafts in oculo. Exp. Neurol., 134, 25–34CrossRef Google Scholar PubMed

Johnson, S. W., Seutin, V. & North, R. A. (1992). Burst firing in dopamine neurons induced by N-methyl-D-aspartate: role of electrogenic sodium pump. Science, 258, 665–7CrossRef Google Scholar PubMed

Kawasaki, H., Mizuseki, K., Nishikawa, S.et al. (2000). Induction of midbrain dopaminergic neurons from ES cells by stromal cell-derived inducing activity. Neuron, 28, 31–40CrossRef Google Scholar PubMed

Kim, J. H., Auerbach, J. M., Rodriguez-Gomez, J. A.et al. (2002). Dopamine neurons derived from embryonic stem cells function in an animal model of Parkinson's disease. Nature, 418, 50–6CrossRef Google Scholar

Kim, K. S., Kim, C. H., Hwang, D. Y.et al. (2003). The orphan nuclear receptor Nurr1 directly transactivates the promotor of the tyrosine hydroxylase gene, but not the dopamine b-hydroxylase gene, in a cell-specific manner. J. Neurochem., 85, 622–34CrossRef Google Scholar

Kopyov, O. V., Jacques, D., Lieberman, A., Duma, C. M. & Rogers, R. L. (1996). Clinical study of fetal mesencephalic intracerebral transplants for the treatment of Parkinson's disease. Cell Transpl., 5, 327–37CrossRef Google Scholar PubMed

Kopyov, O. V., Jacques, D. S., Lieberman, A., Duma, C. M. & Rogers, R. L. (1997). Outcome following intrastriatal fetal mesencephalic grafts for Parkinson's patients is directly related to the volume of grafted tissue. Exp. Neurol., 146, 536–45CrossRef Google Scholar PubMed

Kordower, J., Freeman, T., Chen, E.et al. (1998). Fetal nigral grafts survive and mediate clinical benefit in a patient with Parkinson's disease. Mov. Disord., 13, 383–93CrossRef Google Scholar

Kordower, J. H., Freeman, T. B., Snow, B. J.et al. (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, 1118–24CrossRef Google Scholar

Kordower, J. H., Rosenstein, J. M., Collier, T. J.et al. (1996). Functional fetal nigral grafts in a patient with Parkinson's disease: chemoanatomic, ultrastructural, and metabolic studies. J. Comp. Neurol., 370, 203–303.0.CO;2-6>CrossRef Google Scholar

Lebel, M., Gauthier, Y., Moreau, A. & Drouin, J. (2001). Pitz3 activates mouse tyrosine hydroxylase promoter via a high-affinity binding site. J. Neurochem., 77, 558–67CrossRef Google Scholar

Lee, C. S., Cenci, M. A., Schulzer, M. & Bjorklund, A. (2000a). Embryonic ventral mesencephalic grafts improve levodopa-induced dyskinesia in a rat model of Parkinson's disease. Brain, 123, 1365–79CrossRef Google Scholar

Lee, S. H., Lumelsky, N., Studer, L., Auerbach, J. M. & McKay, R. D. (2000b). Efficient generation of midbrain and hindbrain neurons from mouse embryonic stem cells. Nat. Biotechnol., 18, 675–9CrossRef Google Scholar

Leigh, K., Elisevich, K. & Rogers, K. A. (1994). Vascularisation and microvascular permeability in solid versus cell-suspension embryonic neural grafts. J. Neurosurg., 81, 272–83CrossRef Google Scholar PubMed

Levivier, M., Dethy, S., Rodesch, F.et al. (1997). Intracerebral transplantation of fetal ventral mesencephalon for patients with advanced Parkinson's disease. Methodology and 6-month to 1-year follow-up in 3 patients. Stereotact. Funct. Neurosurg., 69, 99–111CrossRef Google Scholar PubMed

Lim, D. A., Tramontin, A. D., Trevejo, J. M. & Alverez-Buylla, A. (2000). Noggin antagonizes BMP signaling to create a niche for adult neurogenesis. Neuron, 28, 713–26CrossRef Google Scholar PubMed

Lindvall, O., Brundin, P., Widner, H.et al. (1990). Grafts of fetal dopamine neurons survive and improve motor function in Parkinson's disease. Science, 247, 574–7CrossRef Google Scholar PubMed

Lindvall, O. & Hagell, P. (2000). Clinical observations after neural transplantation in Parkinson's disease. Prog. Brain Res., 127, 299–320CrossRef Google Scholar PubMed

Lindvall, O., Rehncrona, S., Gustavi, B.et al. (1988). Fetal dopamine-rich mesencephalic grafts in Parkinson's disease. Lancet, II, 1483–4CrossRef Google Scholar

Lindvall, O., Rehncrona, S., Brundin, P.et al. (1989). Human fetal dopamine neurons grafted into the striatum in two patients with severe Parkinson's disease. A detailed account of methodology and a 6-month follow-up. Arch. Neurol., 46, 615–31CrossRef Google Scholar

Lindvall, O., Widner, H., Rehncrona, S.et al. (1992). Transplantation of fetal dopamine neurons in Parkinson's disease: one-year clinical and neurophysiological observations in two patients with putaminal implants. Ann. Neurol., 31, 155–65CrossRef Google Scholar PubMed

Ljungberg, T., Apicella, P. & Schultz, W. (1992). Responses of monkey dopamine neurons during learning of behavioral reactions. J. Neurophysiol., 67, 145–63CrossRef Google Scholar PubMed

Ma, Y., Feigin, A., Dhawan, V.et al. (2002). Dyskinesia after fetal cell transplantation for parkinsonism: a PET study. Ann. Neurol., 52, 628–34CrossRef Google Scholar PubMed

Madrazo, I., Leon, V. & Torres, C. (1988). Transplantation of fetal substantia nigra and adrenal medulla to the caudate putamen in two patients with Parkinson's disease. N. Engl. J. Med., 318, 51Google Scholar PubMed

Mahalik, T., Finger, T., Stromberg, I. & Olson, L. (1985). Substantia nigra transplants into denervated striatum of the rat: ultrastructure of graft and host interconnections. J. Comp. Neurol., 240, 60–70CrossRef Google Scholar PubMed

Mandel, R., Rendahl, K., Spratt, S., Snyder, R., Cohen, L. & Leff, S. (1998). Characterization of intrastriatal recombinant adeno-associated virus-mediated gene transfer of human tyrosine hydroxylase and human GTP-cyclohydrolase I in a rat model of Parkinson's disease. J. Neurosci., 18, 4271–84CrossRef Google Scholar

Marsden, C. D. (1982). Basal ganglia disease. Lancet, II (8308), 1141–7CrossRef Google Scholar

Mayer, E., Fawcett, J. W. & Dunnett, S. B. (1993). Basic fibroblast growth factor promotes the survival of embryonic ventral mesencephalic dopaminergic neurons. II. Effects on nigral transplants in vivo. Neuroscience, 56, 389–98CrossRef Google Scholar PubMed

McCaffery, P. & Drager, U. C. (1994). High levels of a retinoic acid-generating dehydrogenase in the meso-telencephalic dopamine system. Proc. Natl Acad. Sci., USA, 91, 7772–6CrossRef Google Scholar PubMed

McMahon, A. P., Joyner, A. L., Bradley, A. & McMahon, J. A. (1992). The midbrain-hindbrain phenotype of Wnt-1-/Wnt-1- mice results from stepwise deletion of engrailed-expressing cells by 9.5 days postcoitum. Cell, 69, 581–95CrossRef Google Scholar PubMed

Mendez, I., Dagher, A. & Hong, M. (2000a). Simultaneous intraputaminal and intranigral fetal dopaminergic grafts in Parkinson's disease: first clinical trials. Exp. Neurol., 164, 464Google Scholar

Mendez, I., Hong, M., Smith, S., Dagher, A. & Desrosiers, J. (2000b). Neural transplantation cannula and microinjector system: experimental and clinical experience. Technical note. J. Neurosurg., 92, 493–9CrossRef Google Scholar

Mendez, I., Dagher, A., Hong, M.et al. (2002a). Simultaneous intrastriatal and intranigral fetal dopaminergic grafts in patients with Parkinson disease: a pilot study. Report of three cases. J. Neurosurg., 96, 589–96CrossRef Google Scholar

Meyer, M., Zimmer, J., Seiler, R. W. & Widmer, H. R. (1999). GDNF increases the density of cells containing calbindin but not of cells containing calretinin in cultured rat and human fetal nigral tissue. Cell Transpl., 8, 25–36CrossRef Google Scholar

Millen, K. J., Wurst, W., Herrup, K. & Joyner, A. L. (1994). Abnormal embryonic cerebellar development and patterning of postnatal foliation in two mouse Engrailed-2 mutants. Development, 120, 695–706Google Scholar PubMed

Molina, H., Quinones-Molina, R., Munoz, J.et al. (1994). Neurotransplantation in Parkinson's disease: from open microsurgery to bilateral stereotactic approach: first clinical trial using microelectrode recording technique. Stereotact. Funct. Neurosurg., 62, 204–8CrossRef Google Scholar PubMed

Montgomery, R., Warner, M., Lum, B. & Spear, P. (1996). Herpes simplex virus-1 entry into cells mediated by a novel member of the TNF/NGF receptor family. Cell, 87, 427–36CrossRef Google Scholar PubMed

Nakamura, T., Dhawan, V., Chaly, T.et al. (2001). Blinded positron emission tomography study of dopamine cell implantation for Parkinson's disease. Ann. Neurol., 50, 181–7CrossRef Google Scholar PubMed

Nakao, N., Ogura, M., Nakai, K. & Itakura, T. (1998). Intrastriatal mesencephalic grafts affect neuronal activity in basal ganglia nuclei and their target structures in a rat model of Parkinson's disease. J. Neurosci., 18, 1806–17CrossRef Google Scholar

Nikkah, G., Cunningham, M. G., Jodicke, A., Knappe, U. & Bjorklund, A. (1994). Improved graft survival and striatal reinnervation by microtransplantation of fetal nigral cell suspensions in the rat Parkinson model. Brain Res., 633, 133–43CrossRef Google Scholar

Nilsson, O. G., Clarke, D. J., Brundin, P. & Bjorklund, A. (1988). Comparison of growth and reinnervation properties of cholinergic neurons from different brain regions grafted to the hippocampus. J. Comp. Neurol., 268, 204–22CrossRef Google Scholar PubMed

Nutt, J. G., Obeso, J. A. & Stocchi, F. (2000). Continuous dopamine-receptor stimulation in advanced Parkinson's disease. Trends Neurosci., 23, S109–15CrossRef Google Scholar PubMed

Olanow, C. W. (2002a). Surgical therapy for Parkinson's disease. Eur. J. Neurol., 9 Suppl 3, 31–9CrossRef Google Scholar

Olanow, C. W. (2002b). Transplantation for Parkinson's disease: pros, cons, and where do we go from here?Mov. Disord., 17, S15Google Scholar

Olanow, C. W. & Obeso, J. A. (2000). Preventing levodopa-induced dyskinesias. Ann. Neurol., 47, 167–78Google Scholar PubMed

Olanow, C. W. & Tatton, W. G. (2000). Etiology and pathogenesis of Parkinson's disease. Annu. Rev. Neurosci., 22, 123–44CrossRef Google Scholar

Onn, S.-P., West, A. R. & Grace, A. A. (2000). Dopamine-mediated regulation of striatal neuronal and network interactions. Trends Neurosci., 23, S45–56CrossRef Google Scholar PubMed

Peschanski, M., Defer, G., N'Guyen, J. P.et al. (1994). Bilateral motor improvement and alteration of L-dopa effect in two patients with Parkinson's disease following intrastriatal transplantation of foetal ventral mesencephalon. Brain, 117 (3), 487–99CrossRef Google Scholar PubMed

Piccini, P., Brooks, D. J., Bjorklund, A.et al. (1999). Dopamine release from nigral transplants visualized in vivo in a Parkinson's patient. Nat. Neurosci., 2, 1137–40CrossRef Google Scholar

Piccini, P., Lindvall, O., Bjorklund, A.et al. (2000). Delayed recovery of movement-related cortical function in Parkinson's disease after striatal dopaminergic grafts. Ann. Neurol., 48, 689–953.0.CO;2-N>CrossRef Google Scholar PubMed

Rakic, P. (2002). Adult neurogenesis in mammals: an identity crisis. J. Neurosci., 22, 614–18CrossRef Google Scholar

Ramachandran, A. C., Bartlett, L. E. & Mendez, I. M. (2002). A multiple target neural transplantation strategy for Parkinson's disease. Rev. Neurosci., 13, 243–56CrossRef Google Scholar PubMed

Redmond, D. E. Jr., Leranth, C., Spencer, D. D.et al. (1990). Fetal neural graft survival. Lancet, 336, 820–2CrossRef Google Scholar PubMed

Sanghera, M. K., Manaye, K., McMahon, A., Sonsalla, P. K. & German, D. C. (1997). Dopamine transporter mRNA levels are high in midbrain neurons vulnerable to MPTP. Neuroreport, 8, 3327–31CrossRef Google Scholar PubMed

Saucedo-Cardenas, O., Quintana-Hau, J. D., Le, W. D.et al. (1998). Nurr1 is essential for the induction of the dopaminergic phenotype and the survival of ventral mesencephalic late dopaminergic precursor neurons. Proc. Natl Acad. Sci., USA, 95, 4013–18CrossRef Google Scholar PubMed

Schultzberg, M., Dunnett, S. B., Bjorklund, A.et al. (1984). Dopamine and cholecystokinin immunoreactive neurones in mesencephalic grafts reinnervating the neostriatum: evidence for selective growth regulation. Neuroscience, 12, 17–32CrossRef Google Scholar PubMed

Schumacher, J. M., Short, M. P., Hyman, B. T., Breakefield, X. O. & Isacson, O. (1991). Intracerebral implantation of nerve growth factor-producing fibroblasts protects striatum against neurotoxic levels of excitatory amino acids. Neuroscience, 45, 561–70CrossRef Google Scholar PubMed

Schumacher, J., Ellias, S., Palmer, E.et al. (2000). Transplantation of embryonic porcine mesencephalic tissue in patients with Parkinson's disease. Neurology, 54, 1042–50CrossRef Google Scholar

Semina, E. V., Ferrell, R. E., Mintz-Hittner, H. A.et al. (1998). A novel homeobox gene PITX3 is mutated in families with autosomal-dominant cataracts and ASMD. Nat. Genet., 19, 167–70CrossRef Google Scholar PubMed

Semina, E. V., Reiter, R. S. & Murray, J. C. (1997). Isolation of a new homeobox gene belonging to the Pitx/Rieg family: expression during lens development and mapping to the aphakia region on mouse chromosome 19. Hum. Mol. Genet., 6, 2109–16CrossRef Google Scholar PubMed

Shimazaki, T., Shingo, T. & Weiss, S. (2001). The ciliary neurotrophic factor/leukemia inhibitory factor/gc130 receptor complex operates in the maintenance of mammalian forebrain neural stem cells. J. Neurosci., 21, 7642–53CrossRef Google Scholar PubMed

Simon, H. H., Saueressig, H., Wurst, W., Goulding, M. D. & O'Leary, D. D. (2001). Fate of midbrain dopaminergic neurons controlled by the engrailed genes. J. Neurosci., 21, 3126–34CrossRef Google Scholar PubMed

Smidt, M. P., Schaick, H. S., Lanctot, C.et al. (1997). A homeodomain gene Ptx3 has highly restricted brain expression in mesencephalic dopaminergic neurons. Proc. Natl Acad. Sci., USA, 94, 13305–10CrossRef Google Scholar PubMed

Smidt, M. P., Asbreuk, C. H., Cox, J. J., Chen, H., Johnson, R. L. & Burbach, J. P. (2000). A second independent pathway for development of mesencephalic dopaminergic neurons requires Lmx1b. Nat. Neurosci., 3, 337–41CrossRef Google Scholar PubMed

Sotelo, C. & Alvarado-Mallart, R. M. (1987). Embryonic and adult neurons interact to allow Purkinje cell replacement in mutant cerebellum. Nature, 327, 421–3CrossRef Google Scholar PubMed

Spencer, D. D., Robbins, R. J., Naftolin, F.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, 1541–8CrossRef Google Scholar PubMed

Strecker, R. E. & Jacobs, B. L. (1985). Substantia nigra dopaminergic unit activity in behaving cats: effects of arousal on spontaneous discharge and sensory evoked activity. Brain Res., 361, 339–50CrossRef Google Scholar

Strecker, R. E., Sharp, T., Brundin, P., Zetterstrom, T., Ungerstedt, U. & Bjorklund, A. (1987). Autoregulation of dopamine release and metabolism by intrastriatal nigral grafts as revealed by intracerebral dialysis. Neuroscience, 22, 169–78CrossRef Google Scholar PubMed

Studer, L., Tabar, V. & McKay, R. D. (1998). Transplantation of expanded mesencephalic precursors leads to recovery in parkinsonian rats. Nat. Neurosci., 1, 290–5CrossRef Google Scholar PubMed

Tornqvist, N., Hermanson, E., Perlmann, T. & Stromberg, I. (2002). Generation of tyrosine hydroxylase-immunoreactive neurons in ventral mesencephalic tissue of Nurr1 deficient mice. Brain Res. Dev. Brain Res., 133, 37–47CrossRef Google Scholar PubMed

Venna, N., Sabin, T., Ordia, J. & Mark, V. (1984). Treatment of severe Parkinson's disease by intraventricular injection of dopamine. Appl. Neurophysiol., 47, 62–4Google Scholar PubMed

Wagner, J., Akerud, P., Castro, D. S.et al. (1999). Induction of a midbrain dopaminergic phenotype in Nurr1-overexpressing neural stem cells by type 1 astrocytes. Nat. Biotechnol., 17, 653–9CrossRef Google Scholar PubMed

Wallen, A. A., Castro, D. S., Zetterstrom, R. H.et al. (2001). Orphan nuclear receptor Nurr1 is essential for Ret expression in midbrain dopamine neurons and in the brain stem. Mol. Cell. Neurosci., 18, 649–63CrossRef Google Scholar

Wenning, G. K., Odin, P., Morrish, P.et al. (1997). Short- and long-term survival and function of unilateral intrastriatal dopaminergic grafts in Parkinson's disease. Ann. Neurol., 42, 95–107CrossRef Google Scholar

Widner, H., Tetrud, J., Rehncrona, S.et al. (1992). Bilateral fetal mesencephalic grafting in two patients with parkinsonism induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. N. Engl. J. Med., 327, 1556–63CrossRef Google Scholar

Wurst, W., Auerbach, A. B. & Joyner, A. L. (1994). Multiple developmental defects in Engrailed-1 mutant mice: an early mid-hindbrain deletion and patterning defects in forelimbs and sternum. Development, 120, 2065–75Google Scholar PubMed

Yamada, T., McGeer, P. L., Baimbridge, K. G. & McGeer, E. G. (1990). Relative sparing in Parkinson's disease of substantia nigra dopamine neurons containing calbindin-D28K. Brain Res., 526, 303–7CrossRef Google Scholar PubMed

Zetterstrom, R. H., Solomin, L., Jansson, L., Hoffer, B. J., Olson, L. & Perlmann, T. (1997). Dopamine neuron agenesis in Nurr1-deficient mice. Science, 276, 248–50CrossRef Google Scholar PubMed

Zetterstrom, T., Brundin, P., Gage, F. H.et al. (1986). In vivo measurement of spontaneous release and metabolism of dopamine from intrastriatal nigral grafts using intracerebral dialysis. Brain Res., 362, 344–9CrossRef Google Scholar

Zetterstrom, T. & Ungerstedt, U. (1984). Effects of apomorphine on the in vivo release of dopamine and its metabolites, studied by brain dialysis. Eur. J. Pharmacol., 97, 29–36CrossRef Google Scholar PubMed

Zurn, A. D., Widmer, H. R. & Aebischer, P. (2001). Sustained delivery of GDNF: towards a treatment for Parkinson's disease. Brain Res., 36, 222–9CrossRef Google Scholar PubMed