Concise Review: Therapeutic Strategies for Parkinson Disease Based on the Modula - 《stemcells》干细胞学杂志干细胞之家



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发表于 2009-3-5 00:59 |只看该作者 |倒序浏览 |打印

作者：Martine Geraertsa, Olga Krylyshkinaa, Zeger Debysera, Veerle Baekelandtb作者单位：aLaboratory for Molecular Virology and Gene Therapy, Katholieke Universiteit Leuven and Interdisciplinary Research Center, Campus Kortrijk, Flanders, Belgium;bLaboratory for Neurobiology and Gene Therapy, Katholieke Universiteit Leuven, Flanders, Belgium

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      【摘要】# l3 ^4 v6 }, s
   Parkinson disease (PD) is a progressive neurodegenerative disorder affecting millions of people worldwide. To date, treatment strategies are mainly symptomatic and aimed at increasing dopamine levels in the degenerating nigrostriatal system. Hope rests upon the development of effective neurorestorative or neuroregenerative therapies based on gene and stem cell therapy or a combination of both. The results of experimental therapies based on transplanting exogenous dopamine-rich fetal cells or glial cell line-derived neurotrophic factor overexpression into the brain of Parkinson disease patients encourage future cell- and gene-based strategies. The endogenous neural stem cells of the adult brain provide an alternative and attractive cell source for neuroregeneration. Prior to designing endogenous stem cell therapies, the possible impact of PD on adult neuronal stem cell pools and their neurogenic potential must be investigated. We review the experimental data obtained in animal models or based on analysis of patients' brains prior to describing different treatment strategies. Strategies aimed at enhancing neuronal stem cell proliferation and/or differentiation in the striatum or the substantia nigra will have to be compared in animal models and selected prior to clinical studies. 0 j. P- j9 ~; z' \
      【关键词】 Neurogenesis Parkinson disease Adult neural stem cell Cell therapy
   INTRODUCTION
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Until the mid-1990s, repair mechanisms in the adult central nervous system (CNS) were generally believed to be restricted to a postmitotic state, involving mechanisms such as sprouting of axon terminals and synaptic reorganization, despite the initial discovery of neurogenesis in postnatal rat brain approximately 40 years ago . Further characterization of the organization of the SVZ and RMS will shed light on the genes involved and the cellular regulatory mechanisms in healthy brain and will eventually help in analyzing the alterations in disease.( ?9 L7 @7 y7 ~7 h6 p. b$ ^9 @
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The organization of the adult SVZ in humans is different from that in other mammalian species. The lateral ventricular wall consists of four layers with various thickness and cell densities: a monolayer of ependymal cells (layer I), a hypocellular gap containing astrocytic processes (layer II), a ribbon of cells composed of astrocytes (layer III), and a transitional zone into the brain parenchyma (layer IV) . These results indicate that in comparison with rodents, precursor cells in the human OB are rare but not completely absent.
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A second region of continuous neurogenesis identified in rodents, monkeys, and humans is located in the SGL of the dentate gyrus from the hippocampus. Neural progenitor cells migrate a short distance into the molecular layer and give rise to mature granular cells, sending axons to the CA3 region and projecting dendrites to the outer molecular layer. They develop electrophysiological properties identical to those of mature granular neurons. To what extent these newly generated neurons contribute to the function of both the hippocampus and olfactory bulb is not completely known, but studies show their importance in the formation of new (olfactory) memories .
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In addition, precursor cells were isolated from several so-called non-neurogenic regions (e.g., retina, optic nerve, hypothalamus, and spinal cord), but although they retain the capacity to differentiate into neurons and glia, these cells showed limited self-renewal potential in cell culture  induce modest levels of neurogenesis in response to selective neuronal death or degeneration. This suggests that either changes in the neurogenic permissiveness activate quiescent precursor cells or that recruitment occurs from neurogenic brain regions. Since this mechanism does not reach full cellular and functional recovery, intelligent manipulation of endogenous stem cell populations may represent an interesting target for future therapeutic applications.
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A thorough understanding of the mechanisms that regulate neurogenesis in normal and diseased brain is essential prior to the potential use of endogenous neural stem cells for brain repair. Alternatively, stem cells isolated from (postmortem) brain tissue . Since we do not know the best stem cell source at this moment, research should proceed in parallel on various cell types.
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The extent of anatomical repair required to achieve significant functional recovery is different in various pathological conditions, depending on underlying factors: the nature of the disease, the identity of neuronal systems involved, and the complexity of networks affected. Demyelinating diseases require specific phenotypic replacement (e.g., oligodendrocytes) and restoration of myelin through cellular interactions. Brain injury following trauma or stroke requires replacement of multiple phenotypes, restorations of local circuits, and long-distance projections. Progressive neurodegenerative diseases, such as Parkinson disease and Huntington disease, require restoration of a specific neuronal phenotype and its afferent-efferent connections. Probably, not all neurological disorders are good candidates for cell-based therapies. Despite the complexity of the human brain structure and function, there is hope that one day cell-based treatments may restore damaged brain functions. Whether transplanted or endogenous stem cells in the brain will be used depends on a rigorous understanding of how to control neurogenesis and integration into neural networks.

In this article, we review the cell-based strategies for Parkinson disease. We provide a short update on the cell transplantation studies and recommend recently published reviews for comprehensive in-depth analysis of these studies . We focus mainly on the fate of endogenous neural stem cells in the brain of Parkinson disease patients and in animal models of Parkinson disease (PD).

Regulation of Embryonic Dopaminergic Differentiation3 o3 K$ S. q* I6 \7 r+ m. G

Successful stem cell therapies, whether based on endogenous stem cells or transplantation, require understanding of the normal pathways guiding neuronal differentiation. During embryonic development, almost all central nervous system neurons are generated under control of local inductive signals. Ventral midbrain dopaminergic neurons are born at mouse embryonic day (E) 10¨C11.5 by precise concentration gradients of both sonic hedgehog (Shh) and fibroblast growth factor 8 (FGF-8) , will help us to understand dopaminergic regeneration during adulthood, facilitating the development of new regenerative therapies for PD.0 s8 V( l# L) r- T
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Cell Transplantation Therapy for Parkinson Disease
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Parkinson disease is the second most common neurodegenerative disorder. The lifetime risk of developing Parkinson disease is 2% for men and 1.3% for women. Although the cause of the disease remains unknown, combinations of genetic and environmental factors are believed to be involved in the pathogenesis of the disease. Idiopathic PD is pathologically hallmarked by the presence of intraneuronal Lewy bodies and a progressive neurodegeneration of dopaminergic neurons in the substantia nigra, resulting in depletion of striatal dopamine. This is clinically manifested in motor dysfunctions such as bradykinesia, hypokinesia, and rigidity, sometimes combined with rest tremor and postural changes .6 b" T3 b: {2 T9 f5 f0 r

Early proof-of-principle of cell-based therapies for neurodegeneration in PD patients was provided by transplantation of human fetal mesencephalic tissue from aborted fetuses, rich in primary dopaminergic neurons, in the putamen or caudate nucleus . Nevertheless, these transplantation studies were important as the first experimental cell-based treatment strategies and provided a revolutionary treatment strategy for neurodegeneration: they proved the usefulness of pursuing cell-based approaches in the treatment of neurodegenerative disorders.

Evidence for Neurogenesis in the Striatum and the Subventricular Zone in PD
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It has recently become clear that the existence of endogenous neurogenesis is opening possibilities for a second cell-based approach in the treatment of neurodegeneration. However, a thorough understanding of the regulation of adult neurogenesis is necessary before attempting to modulate and recruit endogenously produced neural precursors for cell replacement. To study the pathophysiology of PD, neurotoxin models (based on methyl-4-phenyl-1,2,3,6-tetrahydropyridine  have been developed. However, we should keep in mind that these models do not fully reconstitute the pathology and disease progression seen in PD patients.

Before the emergence of the stem cell field, there was already evidence that the brains of PD patients and of PD animal models were subject to changes associated with cell plasticity. First, neuronal death in neurodegenerative diseases . The increase in TH-positive cells is believed to be a compensatory response, where a phenotypic switch takes place in striatal neurons, to restore dopamine levels because of the absence of dopaminergic inputs. However, with the new concept of neurogenesis in mind, these results may have to be reconsidered. It is possible that both TH-positive and astroglial cells are either newly generated from precursor cells in the striatum or have migrated from the SVZ. Finding a way to influence cell proliferation, migration, and differentiation (e.g., promoting neuronal differentiation and suppressing astroglial) might help in the development of treatments for PD and other brain disorders.2 Q$ u# E2 n( T$ p* ^

Early after MPTP lesioning, 5-bromo-2'-deoxyuridine (BrdU) labeling of proliferating cells demonstrated a significant increase of labeled cells in the striatum of adult mice. These cells mainly differentiated into mature astroglial cells, participating in the injury-induced glial reaction .
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The effect of the dopamine D2 receptor blocker haloperidol on neurogenesis is more contradictory. Studies report a decreased cell proliferation in the SVZ of early postnatal rats . Hence, the effect of dopamine on SVZ precursors may depend on several factors, including a direct effect through interaction with dopamine receptors and an indirect effect through growth factor release. However, the dopamine receptor subtype expressed by NSCs or progenitor cells may change after brain insults. Together, these studies imply the dopaminergic control of the adult SVZ through the nigrostriatal pathway.$ s  |0 @7 a8 {0 Y) C

Dopamine has also been suggested to be an important regulator of adult neurogenesis in both the OB and hippocampus. Results from animal experiments indicate that olfactory neurogenesis is important for odor memory and hippocampal neurogenesis for mood and mnestic functions , impaired neurogenesis may also be important in the development of hyposmia. This raises the important question of whether reduced neurogenesis might contribute to the development of Parkinson disease symptoms.
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In an -synuclein transgenic mouse model for PD, where no dopaminergic cell death occurs, endogenous neurogenesis in the SVZ and SGZ was reported to be impaired because of reduced survival of neuronal precursors . Together, these results indicate that not only dopamine but also other disease-related mechanisms may contribute in decreased neurogenesis in Parkinson disease.# f  H6 g/ I( S: h% d- R
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Evidence for Endogenous Dopaminergic Neurogenesis in the Substantia Nigra in PD4 J  Z, X/ m' H* H# j1 i

Whether dopaminergic neurogenesis occurs in the adult substantia nigra in normal brain or in PD animal models is still a matter of debate. The controversy may be due to methodological differences between the studies reported (BrdU dose, section thickness, etc.). On the one hand, it has been postulated that dopaminergic differentiation occurs at a very low level in the substantia nigra (SN) of healthy mice and that this process increases after MPTP lesioning . Moreover, striatal innervation from these cells and long-term improvement in locomotor function demonstrate that pharmacological intervention by changing environmental signals may have important implications in the design of novel treatment strategies for PD.# ]  k' o3 t  j" S2 x& X

In the substantia nigra of PD patients, cells expressing PSA, a marker for immature neurons, were detected, which sometimes colabeled with TH .' ^& H: n9 x( |- @

Therapeutic Strategies Based on Endogenous Neurogenesis

The response of endogenous neural precursors in PD animal models is complex. Because of partial dopaminergic control of the SVZ progenitors in the vicinity of the degenerating axon terminals, proliferation in the SVZ decreases, whereas new astroglia are generated in the striatum. Progenitors in the substantia nigra, in the vicinity of degenerating dopaminergic neurons, respond by increasing proliferation (Fig. 1) with minor dopaminergic differentiation. This implies that different regulatory mechanisms mediated by the changes in the local microenvironment result in different responses in both brain regions. Hence, different therapeutic strategies may be necessary for both regions.

Figure 1. Overview of responsive regions of cell proliferation in rat and mouse models of Parkinson disease. Areas in red correspond to regions of decreased cell proliferation, whereas areas in green correspond to regions of increased cell proliferation. Neurogenesis in the subventricular zone of the lateral ventricle and the DG of the hippocampus is decreased. Less proliferative cells were detected in the Gr. However, the amount of dopaminergic neurons in the Gl is increased. Neurotoxic lesioning also results in glial cell proliferation in the striatum and increased cell proliferation in the SN. Whether neurogenesis is occurring in the SN is still a matter of debate. Abbreviations: cc, corpus callosum; CPu, caudate putamen (striatum); DG, dentate gyrus; EPl, external plexiform layer of olfactory bulb; Gl, glomerular layer of olfactory bulb; Gr, granular cell layer of olfactory bulb; IPl, internal plexiform layer of olfactory bulb; LV, lateral ventricle; LR4V, lateral recess of the 4th ventricle; Mi, mitral cell layer of olfactory bulb; SN, substantia nigra.# Z3 ]1 R* o+ v- H+ O# X  y  _
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As long as no causal therapy for PD can be designed, it will remain important to increase dopamine levels in the striatum. Based on the fetal transplantation studies, it has been estimated that only 2%¨C4% of the normal number of dopaminergic neurons that innervate the striatum should be restored for the first signs of functional recovery to occur in rodents with nigrostriatal lesions .

Successful endogenous stem cell-based therapy has to result in efficient progenitor cell proliferation, dopaminergic differentiation, and survival of newly generated cells. Therefore, different strategies can be pursued: It may be feasible to generate dopaminergic neurons in the striatum by either recruitment of endogenous progenitors from the SVZ or stimulation of resident cells in the striatum. Next, since the SN harbors proliferating cells, it may be feasible to stimulate differentiation into dopaminergic neurons. However, restoration of nigrostriatal projections may be the major challenge here. To date, the optimal approach for endogenous stem cell therapy is not known. Stimulation of cell proliferation or induction of dopaminergic differentiation may be mediated by viral vector-mediated local overexpression of either growth or transcription factors or by pharmacological intervention. Alternatively, alteration of the local microenvironment by overexpression of growth factors may increase cell survival and help in dopaminergic differentiation. Since it is difficult to predict whether intrinsic and extrinsic signals or a combination of both will be necessary, careful investigation in animal models of Parkinson disease is required to shed light on the feasibility of cell therapy in combination with gene or pharmacotherapy to induce dopaminergic differentiation.9 b4 y3 ~0 d* O. {
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What are the results described so far? In animals, SVZ progenitors can be recruited to the striatum after administration of several growth factors (e.g., transforming growth factor- , providing further evidence for the restorative actions of this growth factor. These initial studies have thus demonstrated that cell recruitment to the striatum is possible in animal models of PD. However, the next challenge lies in stimulating the proliferated cells to differentiate into dopamine-secreting cells and demonstrating a clear correlation between dopaminergic differentiation and functional recovery.
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In addition to growth factors, neurotransmitters such as dopamine are reported to play a role in the control of embryonic and adult neurogenesis. As mentioned before, dopamine receptor stimulation may be an interesting strategy to induce cell proliferation. Stimulation of the dopamine D3 receptor by a preferential agonist, 7-OH-DPAT, not only increased cell proliferation in the SVZ and striatum . Further testing in different animal models of PD will be of much importance in shedding light on the pharmacologic intervention with progenitor-specific agonists.; b( E8 z7 L5 L+ {
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Several characteristic transcription factors have been described to be involved in the maturation of dopaminergic neurons, such as Nurr-1, Pitx3, Engrailed, and Lmx1b . Alternatively, overexpression in precursors in the substantia nigra might increase dopaminergic differentiation. It will be of interest to study the role of these differentiation factors with or without additional growth factors after dopaminergic denervation in animal models of PD.; s6 S% G& H( F( n1 v

Conclusion
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The discovery of sustained neurogenesis in the adult brain has opened attractive therapeutic perspectives for a variety of brain disorders, including neurodegenerative diseases. Endogenous stem cell therapy for Parkinson disease offers several potential advantages over other cell-based treatment strategies: immunological reactions are circumvented, and ethical issues surrounding the use of embryonic stem cells are avoided. However, many challenges still need to be overcome before this strategy can be brought into the clinic. There is still a great need of basic research on the mechanisms (both intrinsic and extrinsic) that control adult neurogenesis. Eventually, new strategies must be tested in the monkey MPTP model, the gold standard for assessment of novel strategies for PD. However, the development of animal models for PD that reproduce the pathophysiology of the human condition more accurately than the currently available models will also help to predict whether experimental treatment strategies hold up in a preclinical setting.1 a" c. F! P& h) ~2 I8 u
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DISCLOSURES$ p8 e- U. @2 P3 t2 X0 P8 l- r
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The authors indicate no potential conflicts of interest.
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ACKNOWLEDGMENTS

This study was financially supported by SBO Grant IWT-30238 of the Flemish Institute supporting Scientific-Technological Research in Industry (IWT), Flemish Fund for Scientific Research (FWO Vlaanderen) Grant G.0164.03, and European Community Grants QLK3-CT-2002-02114 (N)EUROPARK and FP6-project DiMI LSHB-CT-2005-512146. M.G. is funded by a grant from the Institute for Promotion of Innovation through Science and Technology in Flanders (IWT-Vlaanderen). V.B. is a postdoctoral fellow of FWO Vlaanderen.
      【参考文献】

Altman J, Das GD. Autoradiographic and histological evidence of postnatal hippocampal neurogenesis in rats. J Comp Neurol 1965;124:319¨C335.

Altman J. Autoradiographic and histological studies of postnatal neurogenesis. IV. Cell proliferation and migration in the anterior forebrain, with special reference to persisting neurogenesis in the olfactory bulb. J Comp Neurol 1969;137:433¨C457.% s' d  s( I9 @' a  N/ h5 v* I

Gage FH. Mammalian neural stem cells. Science 2000;287:1433¨C1438.4 S' |# [7 j& o0 v
& u1 E1 a0 H! o
Ming GL, Song H. Adult neurogenesis in the mammalian central nervous system. Annu Rev Neurosci 2005;28:223¨C250.2 a& c  U+ L9 O# S9 F3 X- H) @
! H2 B4 r# y0 o
Alvarez-Buylla A, Lim DA. For the long run: Maintaining germinal niches in the adult brain. Neuron 2004;41:683¨C686.

Hack MA, Saghatelyan A, de Chevigny A et al. Neuronal fate determinants of adult olfactory bulb neurogenesis. Nat Neurosci 2005;8:865¨C872.+ ]" L$ X$ g+ u

Quinones-Hinojosa A, Sanai N, Soriano-Navarro M et al. Cellular composition and cytoarchitecture of the adult human subventricular zone: A niche of neural stem cells. J Comp Neurol 2006;494:415¨C434.
1 h; c) m) I  ?0 T  J1 f) {: o
Sanai N, Tramontin AD, Quinones-Hinojosa A et al. Unique astrocyte ribbon in adult human brain contains neural stem cells but lacks chain migration. Nature 2004;427:740¨C744./ V; d. x4 r4 r
# M8 r( E$ a3 p( h. g) e, _. H, G
Bedard A, Parent A. Evidence of newly generated neurons in the human olfactory bulb. Brain Res Dev Brain Res 2004;151:159¨C168.1 `1 n2 R: o% L- i

Prickaerts J, Koopmans G, Blokland A et al. Learning and adult neurogenesis: Survival with or without proliferation? Neurobiol Learn Mem 2004;81:1¨C11.

Doetsch F, Hen R. Young and excitable: The function of new neurons in the adult mammalian brain. Curr Opin Neurobiol 2005;15:121¨C128.
# x) K8 p- D! A4 U
Reynolds BA, Weiss S. Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system. Science 1992;255:1707¨C1710.8 m% }. ~8 D( _3 T4 W
  C- c2 k  ?, t1 L3 C! t- f
Palmer TD, Markakis EA, Willhoite AR et al. Fibroblast growth factor-2 activates a latent neurogenic program in neural stem cells from diverse regions of the adult CNS. J Neurosci 1999;19:8487¨C8497.5 O4 H7 k" [0 `1 R: b

Palmer TD, Ray J, Gage FH. FGF-2-responsive neuronal progenitors reside in proliferative and quiescent regions of the adult rodent brain. Mol Cell Neurosci 1995;6:474¨C486.

Lie DC, Dziewczapolski G, Willhoite AR et al. The adult substantia nigra contains progenitor cells with neurogenic potential. J Neurosci 2002;22:6639¨C6649.1 \. J/ K( T' Y0 S2 |4 o; A4 A
) }8 L( |3 U. M0 C; I; z% x2 y
Shihabuddin LS, Ray J, Gage FH. FGF-2 is sufficient to isolate progenitors found in the adult mammalian spinal cord. Exp Neurol 1997;148:577¨C586.* @, Y* j; r% e  R# ]/ e
, Q0 p* p6 Q0 I0 k
Tropepe V, Coles BL, Chiasson BJ et al. Retinal stem cells in the adult mammalian eye. Science 2000;287:2032¨C2036.
: E8 ]7 g0 n) {% d
Weiss S, Dunne C, Hewson J et al. Multipotent CNS stem cells are present in the adult mammalian spinal cord and ventricular neuroaxis. J Neurosci 1996;16:7599¨C7609.
1 i) `% r  @- p( U1 ~1 `
Rietze R, Poulin P, Weiss S. Mitotically active cells that generate neurons and astrocytes are present in multiple regions of the adult mouse hippocampus. J Comp Neurol 2000;424:397¨C408.

Arvidsson A, Collin T, Kirik D et al. Neuronal replacement from endogenous precursors in the adult brain after stroke. Nat Med 2002;8:963¨C970.

Parent JM, Vexler ZS, Gong C et al. Rat forebrain neurogenesis and striatal neuron replacement after focal stroke. Ann Neurol 2002;52:802¨C813.
+ C+ K8 a2 `( `- I+ F: p( r
Magavi SS, Leavitt BR, Macklis JD. Induction of neurogenesis in the neocortex of adult mice. Nature 2000;405:951¨C955.
' |* k* r, Q4 Z8 w4 g8 O
Chen J, Magavi SS, Macklis JD. Neurogenesis of corticospinal motor neurons extending spinal projections in adult mice. Proc Natl Acad Sci U S A 2004;101:16357¨C16362.+ [) L3 `9 \/ E6 V

Nakatomi H, Kuriu T, Okabe S et al. Regeneration of hippocampal pyramidal neurons after ischemic brain injury by recruitment of endogenous neural progenitors. Cell 2002;110:429¨C441.+ k3 k* I4 i7 o7 {$ o
# _. C0 _$ m! u9 ^1 l$ o
Feldmann RE Jr, Mattern R. The human brain and its neural stem cells postmortem: From dead brains to live therapy. Int J Legal Med 2005;1¨C11.
# o  m3 A4 F. H0 Y
Ben-Hur T. Human embryonic stem cells for neuronal repair. Isr Med Assoc J 2006;8:122¨C126.+ p3 x. E5 w1 Z8 H2 E
  V5 o& Z. z( m$ b9 v
Krabbe C, Zimmer J, Meyer M. Neural transdifferentiation of mesenchymal stem cells: A critical review. APMIS 2005;113:831¨C844.. c/ L3 O2 C2 k
* ]2 V+ G& a6 {- ^
Kokai LE, Rubin JP, Marra KG. The potential of adipose-derived adult stem cells as a source of neuronal progenitor cells. Plast Reconstr Surg 2005;116:1453¨C1460.; J: `" i. \) X- t; j( U6 I
1 V4 `( J* O* b; S" Y& `
Consiglio A, Gritti A, Dolcetta D et al. Robust in vivo gene transfer into adult mammalian neural stem cells by lentiviral vectors. Proc Natl Acad Sci U S A 2004;101:14835¨C14840.( _# o9 H7 _! T3 o/ y

van Praag H, Schinder AF, Christie BR et al. Functional neurogenesis in the adult hippocampus. Nature 2002;415:1030¨C1034.
$ {7 j# X8 @' K6 v
Geraerts M, Eggermont K, Hernandez-Acosta P et al. Lentiviral vectors mediate efficient and stable gene transfer in adult neural stem cells in vivo. Hum Gene Ther 2006;17:635¨C650.' i; z6 E* @+ |+ W; Q
) X( w. k# q$ Y+ G" `6 C
Fillmore HL, Holloway KL, Gillies GT. Cell replacement efforts to repair neuronal injury: A potential paradigm for the treatment of Parkinson's disease. NeuroRehabilitation 2005;20:233¨C242.0 d* d  }* n+ N4 g+ u; ~/ w

Lindvall O, Bjorklund A. Cell therapy in Parkinson's disease. NeuroRx 2004;1:382¨C393.: q/ U" N* s8 n3 ^3 P
1 r' ~& o# ^# o9 s1 E% ^7 S
Roussa E, Krieglstein K. Induction and specification of midbrain dopaminergic cells: Focus on SHH, FGF8, and TGF-beta. Cell Tissue Res 2004;318:23¨C33.; B! b/ N: C( U) T) A0 ]! R  u! Q# y8 Z
, v9 j% E# D+ [. \5 y& v
Andersson E, Tryggvason U, Deng Q et al. Identification of intrinsic determinants of midbrain dopamine neurons. Cell 2006;124:393¨C405.! @) m% H7 R) t% Y# P- Y# a
3 {1 Q$ k3 ^' t' S4 j
Simon HH, Saueressig H, Wurst W et al. Fate of midbrain dopaminergic neurons controlled by the engrailed genes. J Neurosci 2001;21:3126¨C3134.

Smidt MP, Asbreuk CH, Cox JJ et al. A second independent pathway for development of mesencephalic dopaminergic neurons requires Lmx1b. Nat Neurosci 2000;3:337¨C341.

Nunes I, Tovmasian LT, Silva RM et al. Pitx3 is required for development of substantia nigra dopaminergic neurons. Proc Natl Acad Sci U S A 2003;100:4245¨C4250.* K1 b- [2 E) A# q

van den Munckhof P, Luk KC, Ste-Marie L et al. Pitx3 is required for motor activity and for survival of a subset of midbrain dopaminergic neurons. Development 2003;130:2535¨C2542.- @/ l. ~5 E. ^$ b3 @3 _

Wallen A, Perlmann T. Transcriptional control of dopamine neuron development. Ann N Y Acad Sci 2003;991:48¨C60.( L5 Z; j' {: g) ~( U

Zetterstrom RH, Solomin L, Jansson L et al. Dopamine neuron agenesis in Nurr1-deficient mice. Science 1997;276:248¨C250.

Barbeau A, Dallaire L, Buu NT et al. New amphibian models for the study of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Life Sci 1985;36:1125¨C1134.5 K" {7 U. o6 f9 X
4 a% A( J8 |' d2 }) z
Endepols H, Schul J, Gerhardt HC et al. 6-Hydroxydopamine lesions in anuran amphibians: A new model system for Parkinson's disease? J Neurobiol 2004;60:395¨C410.; r; C$ J1 b4 ^' b; f. a' D

Fahn S. Description of Parkinson's disease as a clinical syndrome. Ann N Y Acad Sci 2003;991:1¨C14.

Braak H, Del Tredici K, Bratzke H et al. Staging of the intracerebral inclusion body pathology associated with idiopathic Parkinson's disease (preclinical and clinical stages). J Neurol 2002;249 (suppl 3):III/1¨C5.
7 |' ^; K' a; m/ R5 ~8 D6 r
Bernheimer H, Birkmayer W, Hornykiewicz O et al. Brain dopamine and the syndromes of Parkinson and Huntington. Clinical, morphological and neurochemical correlations. J Neurol Sci 1973;20:415¨C455.

Braak H, Ghebremedhin E, Rub U et al. Stages in the development of Parkinson's disease-related pathology. Cell Tissue Res 2004;318:121¨C134.

Stocchi F. Optimising levodopa therapy for the management of Parkinson's disease. J Neurol 2005;252 (suppl 4):IV43¨CIV48.& A0 i5 U7 [" D' R) S
) l; _+ R* j) m- I
Schapira AH. Present and future drug treatment for Parkinson's disease. J Neurol Neurosurg Psychiatry 2005;76:1472¨C1478.9 T% ^) e( C4 q+ [
9 N- B9 z4 N, k- v) |
Lindvall O, Kokaia Z, Martinez-Serrano A. Stem cell therapy for human neurodegenerative disorders: How to make it work. Nat Med 2004;10:S42¨CS50.
' M3 Z  E; H& V& W
Piper M, Abrams GM, Marks WJ Jr. Deep brain stimulation for the treatment of Parkinson's disease: Overview and impact on gait and mobility. NeuroRehabilitation 2005;20:223¨C232.6 ~* _3 r4 ^2 q7 R* n. K

Snyder BJ, Olanow CW. Stem cell treatment for Parkinson's disease: An update for 2005. Curr Opin Neurol 2005;18:376¨C385.

Bove J, Prou D, Perier C et al. Toxin-induced models of Parkinson's disease. NeuroRx 2005;2:484¨C494.  r2 {) W  ]2 E- ^( C! G7 W
1 P* m) U/ r/ p* R
Fleming SM, Fernagut PO, Chesselet MF. Genetic mouse models of parkinsonism: Strengths and limitations. NeuroRx 2005;2:495¨C503.

Kirik D, Bjorklund A. Modeling CNS neurodegeneration by overexpression of disease-causing proteins using viral vectors. Trends Neurosci 2003;26:386¨C392.' q3 }/ a4 y$ {; \$ x
- s0 j/ r4 p& J; j
Lauwers E, Debyser Z, Van Dorpe J et al. Neuropathology and neurodegeneration in rodent brain induced by lentiviral vector-mediated overexpression of alpha-synuclein. Brain Pathol 2003;13:364¨C372.
+ G$ W" q2 P' T3 x0 N# m0 ~( l
Hirsch EC, Breidert T, Rousselet E et al. The role of glial reaction and inflammation in Parkinson's disease. Ann N Y Acad Sci 2003;991:214¨C228.
5 o. E' d3 u* l, U' ?
Rodrigues RW, Gomide VC, Chadi G. Astroglial and microglial reaction after a partial nigrostriatal degeneration induced by the striatal injection of different doses of 6-hydroxydopamine. Int J Neurosci 2001;109:91¨C126.( B3 W1 O; {2 O5 L7 S, h0 L0 }

Ho A, Blum M. Induction of interleukin-1 associated with compensatory dopaminergic sprouting in the denervated striatum of young mice: Model of aging and neurodegenerative disease. J Neurosci 1998;18:5614¨C5629.
" n; B$ s( g; |$ x; G0 j0 ^
Cossette M, Lecomte F, Parent A. Morphology and distribution of dopaminergic neurons intrinsic to the human striatum. J Chem Neuroanat 2005;29:1¨C11.6 I, K% p" W  N& t8 e8 a' J

Baker H, Kobayashi K, Okano H et al. Cortical and striatal expression of tyrosine hydroxylase mRNA in neonatal and adult mice. Cell Mol Neurobiol 2003;23:507¨C518." {0 q2 i! L) G# m

Tashiro Y, Sugimoto T, Hattori T et al. Tyrosine hydroxylase-like immunoreactive neurons in the striatum of the rat. Neurosci Lett 1989;97:6¨C10.. C2 p7 u- X9 w
5 h+ B, f- }) p" O! b* K
Dubach M, Schmidt R, Kunkel D et al. Primate neostriatal neurons containing tyrosine hydroxylase: Immunohistochemical evidence. Neurosci Lett 1987;75:205¨C210.
- ^+ q6 _. M, c8 b
Betarbet R, Turner R, Chockkan V et al. Dopaminergic neurons intrinsic to the primate striatum. J Neurosci 1997;17:6761¨C6768.0 X0 s# P2 y( J+ m# C( `
5 [! U( u* i* f2 M+ m+ {% T7 J
Palfi S, Leventhal L, Chu Y et al. Lentivirally delivered glial cell line-derived neurotrophic factor increases the number of striatal dopaminergic neurons in primate models of nigrostriatal degeneration. J Neurosci 2002;22:4942¨C4954.5 `" O! H" a% p5 u, `
- @3 Y  Y" w7 B2 i
Meredith GE, Farrell T, Kellaghan P et al. Immunocytochemical characterization of catecholaminergic neurons in the rat striatum following dopamine-depleting lesions. Eur J Neurosci 1999;11:3585¨C3596.
2 y* n; T0 q* {. ]* H  L0 Q
Petroske E, Meredith GE, Callen S et al. Mouse model of Parkinsonism: A comparison between subacute MPTP and chronic MPTP/probenecid treatment. Neuroscience 2001;106:589¨C601.

Mao L, Lau YS, Petroske E et al. Profound astrogenesis in the striatum of adult mice following nigrostriatal dopaminergic lesion by repeated MPTP administration. Brain Res Dev Brain Res 2001;131:57¨C65.1 }* D0 U3 P' V- S/ d" V* ]/ S  b8 [7 g

Porritt MJ, Batchelor PE, Hughes AJ et al. New dopaminergic neurons in Parkinson's disease striatum. Lancet 2000;356:44¨C45.
# e. C% X3 C4 |
Kay JN, Blum M. Differential response of ventral midbrain and striatal progenitor cells to lesions of the nigrostriatal dopaminergic projection. Dev Neurosci 2000;22:56¨C67." a+ Z0 M. k  _" w" G1 z5 e; }; I# c- u
9 Z! ?  }: j1 v7 M2 l
Tande D, Hoglinger G, Debeir T et al. New striatal dopamine neurons in MPTP-treated macaques result from a phenotypic shift and not neurogenesis. Brain 2006;129:1194¨C1200.  f3 w* Z& n: m' I

Hoglinger GU, Rizk P, Muriel MP et al. Dopamine depletion impairs precursor cell proliferation in Parkinson disease. Nat Neurosci 2004;7:726¨C735.0 E6 d% A- R: ?1 F1 u: Z# w
0 v# R( L$ M+ ~5 U/ V/ q4 s
Baker SA, Baker KA, Hagg T. Dopaminergic nigrostriatal projections regulate neural precursor proliferation in the adult mouse subventricular zone. Eur J Neurosci 2004;20:575¨C579.
! `: i# Q+ P; Z6 k# ^3 J  Z
Freundlieb N, Francois C, Tande D et al. Dopaminergic substantia nigra neurons project topographically organized to the subventricular zone and stimulate precursor cell proliferation in aged primates. J Neurosci 2006;26:2321¨C2325.8 W( z- c, I. @! u& d7 t, d, t
' h/ {1 ^7 V: y0 O# F, Y
Coronas V, Bantubungi K, Fombonne J et al. Dopamine D3 receptor stimulation promotes the proliferation of cells derived from the post-natal subventricular zone. J Neurochem 2004;91:1292¨C1301.0 G( H# o! a/ J0 \3 Y

Diaz J, Ridray S, Mignon V et al. Selective expression of dopamine D3 receptor mRNA in proliferative zones during embryonic development of the rat brain. J Neurosci 1997;17:4282¨C4292.

Van Kampen JM, Hagg T, Robertson HA. Induction of neurogenesis in the adult rat subventricular zone and neostriatum following dopamine D receptor stimulation. Eur J Neurosci 2004;19:2377¨C2387.

Baker SA, Baker KA, Hagg T. D3 dopamine receptors do not regulate neurogenesis in the subventricular zone of adult mice. Neurobiol Dis 2005;18:523¨C527.) f7 V1 {' K0 w9 I* b( Z
# m/ i8 z( M& g6 Z. `: H
Backhouse B, Barochovsky O, Malik C et al. Effects of haloperidol on cell proliferation in the early postnatal rat brain. Neuropathol Appl Neurobiol 1982;8:109¨C116.5 }1 ]8 m! w2 @# q  `0 m. u

Wakade CG, Mahadik SP, Waller JL et al. Atypical neuroleptics stimulate neurogenesis in adult rat brain. J Neurosci Res 2002;69:72¨C79.; }" x' p2 b( R9 I  U- Y& m" I
! S% t# b2 _! O
Kippin TE, Kapur S, van der Kooy D. Dopamine specifically inhibits forebrain neural stem cell proliferation, suggesting a novel effect of antipsychotic drugs. J Neurosci 2005;25:5815¨C5823.
+ j8 B* z6 i' _% _
Nagatsu T, Mogi M, Ichinose H et al. Changes in cytokines and neurotrophins in Parkinson's disease. J Neural Transm Suppl 2000;277¨C290.

Ingham CA, Hood SH, van Maldegem B et al. Morphological changes in the rat neostriatum after unilateral 6-hydroxydopamine injections into the nigrostriatal pathway. Exp Brain Res 1993;93:17¨C27.

Yamada M, Onodera M, Mizuno Y et al. Neurogenesis in olfactory bulb identified by retroviral labeling in normal and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated adult mice. Neuroscience 2004;124:173¨C181." \; C& g7 O+ q5 J
' g$ Y6 k0 ?5 m
Winner B, Geyer M, Couillard-Despres S et al. Striatal deafferentation increases dopaminergic neurogenesis in the adult olfactory bulb. Exp Neurol 2006;197:113¨C121.
1 o/ x" G3 I' [' z$ O
Huisman E, Uylings HB, Hoogland PV. A 100% increase of dopaminergic cells in the olfactory bulb may explain hyposmia in Parkinson's disease. Mov Disord 2004;19:687¨C692.* P! ^% H1 Z4 r  c4 u

Berendse HW, Booij J, Francot CM et al. Subclinical dopaminergic dysfunction in asymptomatic Parkinson's disease patients' relatives with a decreased sense of smell. Ann Neurol 2001;50:34¨C41.% R4 W$ Z0 X- P0 t
! p1 Y7 v1 g( S
Oertel WH, Hoglinger GU, Caraceni T et al. Depression in Parkinson's disease. An update. Adv Neurol 2001;86:373¨C383.

Pillon B, Ertle S, Deweer B et al. Memory for spatial location in ¡®de novo¡¯ parkinsonian patients. Neuropsychologia 1997;35:221¨C228.
2 ~) D- Z5 C2 L6 ^6 t5 U
Braak H, Tredici KD, Rub U et al. Staging of brain pathology related to sporadic Parkinson's disease. Neurobiol Aging 2003;24:197¨C211.

Hoogland PV, van den Berg R, Huisman E. Misrouted olfactory fibres and ectopic olfactory glomeruli in normal humans and in Parkinson and Alzheimer patients. Neuropathol Appl Neurobiol 2003;29:303¨C311.
; ?) f9 V* w8 y% x4 d; X# ^% O7 M
Winner B, Lie DC, Rockenstein E et al. Human wild-type alpha-synuclein impairs neurogenesis. J Neuropathol Exp Neurol 2004;63:1155¨C1166.
* H$ u5 _* W% J  F
Zhao M, Momma S, Delfani K et al. Evidence for neurogenesis in the adult mammalian substantia nigra. Proc Natl Acad Sci U S A 2003;100:7925¨C7930.
) ]; F& L( u3 }- Z1 n. E( N
Shan X, Chi L, Bishop M et al. Enhanced de novo neurogenesis and dopaminergic neurogenesis in the substantia nigra of 1-methyl-4-phyenyl-1,2,3,6-tetrahydropyridine-induced Parkinson's disease-like mice. STEM CELLS 2006;24:1280¨C1287.1 y& e! ?2 y8 E' G5 R" y3 H

Frielingsdorf H, Schwarz K, Brundin P et al. No evidence for new dopaminergic neurons in the adult mammalian substantia nigra. Proc Natl Acad Sci U S A 2004;101:10177¨C10182.5 ?" t5 x- L, t5 A
5 ~$ \6 s7 b! C8 ]3 ~
Steiner B, Winter C, Hosman K et al. Enriched environment induces cellular plasticity in the adult substantia nigra and improves motor behavior function in the 6-OHDA rat model of Parkinson's disease. Exp Neurol 2006;199:291¨C300.
3 q# P( n4 W* q9 b9 [8 v
Hermann A, Maisel M, Wegner F et al. Multipotent neural stem cells from the adult tegmentum with dopaminergic potential develop essential properties of functional neurons. STEM CELLS 2006;24:949¨C964.0 J( i6 E/ \* y7 b4 t; P# E# d, P
  N! e' z+ `6 O, I1 g1 p2 j
Van Kampen JM, Robertson HA. A possible role for dopamine D3 receptor stimulation in the induction of neurogenesis in the adult rat substantia nigra. Neuroscience 2005;136:381¨C386.

Van Kampen JM, Eckman CB. Dopamine D3 receptor agonist delivery to a model of Parkinson's disease restores the nigrostriatal pathway and improves locomotor behavior. J Neurosci 2006;26:7272¨C7280.

Yoshimi K, Ren YR, Seki T et al. Possibility for neurogenesis in substantia nigra of parkinsonian brain. Ann Neurol 2005;58:31¨C40.
7 Y$ A4 k. v/ g1 q+ f
Charles P, Reynolds R, Seilhean D et al. Re-expression of PSA-NCAM by demyelinated axons: An inhibitor of remyelination in multiple sclerosis? Brain 2002;125:1972¨C1979.7 h+ f  G; s# g1 G
. e" F/ W; q+ i5 l' R8 ^
Nomura T, Yabe T, Rosenthal ES et al. PSA-NCAM distinguishes reactive astrocytes in 6-OHDA-lesioned substantia nigra from those in the striatal terminal fields. J Neurosci Res 2000;61:588¨C596.8 ^2 h1 s" T+ e- s) D" ]8 K

Mohapel P, Frielingsdorf H, Haggblad J et al. Platelet-derived growth factor (PDGF-BB) and brain-derived neurotrophic factor (BDNF) induce striatal neurogenesis in adult rats with 6-hydroxydopamine lesions. Neuroscience 2005;132:767¨C776." V9 q$ \' f% }4 Z

Fallon J, Reid S, Kinyamu R et al. In vivo induction of massive proliferation, directed migration, and differentiation of neural cells in the adult mammalian brain. Proc Natl Acad Sci U S A 2000;97:14686¨C14691.) g* P) ~7 y$ y' W3 I

Benraiss A, Chmielnicki E, Lerner K et al. Adenoviral brain-derived neurotrophic factor induces both neostriatal and olfactory neuronal recruitment from endogenous progenitor cells in the adult forebrain. J Neurosci 2001;21:6718¨C6731.

Cooper O, Isacson O. Intrastriatal transforming growth factor alpha delivery to a model of Parkinson's disease induces proliferation and migration of endogenous adult neural progenitor cells without differentiation into dopaminergic neurons. J Neurosci 2004;24:8924¨C8931.6 g! o# D. h4 ^# M6 `

Chen Y, Ai Y, Slevin JR et al. Progenitor proliferation in the adult hippocampus and substantia nigra induced by glial cell line-derived neurotrophic factor. Exp Neurol 2005;196:87¨C95.

Verfaillie CM, Schwartz R, Reyes M et al. Unexpected potential of adult stem cells. Ann N Y Acad Sci 2003;996:231¨C234.

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