Dokument

Summary:
Hyposmia, often preceding the cardinal motor symptoms, such as bradykinesia, rigidity, tremor at rest and postural instability, is frequently reported in PD. This symptom appears to be related to an increased number of dopamine neurons in the periglomerular layer (PGL) of the OB. In the histological study, we have investigated the survival and neuronal differentiation of NPC in the OB, following L-DOPA and/or Selegiline in a unilateral, intranigral 6-OHDA lesion model in mice. Our data show that the number of NPC in the SVZ is decreased after 6-OHDA lesion, while there is no difference from control in lesioned mice with Selegiline or L-DOPA treatment. Moreover, the monoamine oxidase-B inhibitor, Selegiline, is able to normalize the number of dopamine neurons by increasing the number of TUNEL+ cell and reverses the dopaminergic differentiation to control in the PGL, while L-DOPA treatment sustains the increased number, by increasing the survival of NPC and upregulating 2-fold dopaminergic differentiation observed in 6-OHDA lesioned animals. In the behavioral study, to understand the olfactory function after 6-OHDA lesion and the effects of Selegiline treatment, six different experimental groups were investigated and performed an olfactory discrimination test. The data show that a delayed olfactory deficit was first appeared 12 weeks post 6-OHDA lesion and the recovery of olfactory function followed a daily, chronic treatment of Selegiline for additional 12 weeks. However, the olfactory dysfunction of the animals relapses again after a 4-week withdrawal of Selegiline treatment. To combine the findings of our studies, we conclude that there is a distinct modulation of newly generated dopamine neurons of the OB after L-DOPA and/or Selegiline treatment. Furthermore, a delayed olfactory deficit was detected after a downregulation of adult neurogenesis, and only a chronic, continuous treatment of Selegiline can reverse the olfactory dysfunction in an acute mouse model of PD. Our findings provide practical implications and stimulate further clinical and preclinical research, bridging the basic knowledge of hyposmia of PD from bench to bedside. Although the relationship of hyposmia and an increased number of dopamine neurons in the OB of PD patients is not well defined yet, the evidence in this study may offer the explanation, that the dysregulation of adult neurogenesis might be one of reasons to cause hyposmia of PD. Moreover, the effects of Selegiline on olfactory function could be a consideration for clinical application. However, further studies are needed to show whether the interaction of dopamine depletion and drug treatment plays a role in olfactory function in PD patients.

Bibliographie / References

1. Mundiñano, I.-C., Caballero, M.-C., Ordóñez, C., Hernandez, M., DiCaudo, C., Marcilla, I., Erro, M.-E., Tuñon, M.-T., Luquin, M.-R., 2011 Increased dopaminergic cells and protein aggregates in the olfactory bulb of patients with neurodegenerative disorders. Acta Neuropathol. 122, 61-74. References 78
2. Fearnley, J. M., Lees, A. J., 1991. Ageing and Parkinson's disease: substantia nigra regional selectivity. Brain. 114 ( Pt 5), 2283-301.
3. Rochefort, C., Gheusi, G., Vincent, J. D., Lledo, P. M., 2002. Enriched odor exposure increases the number of newborn neurons in the adult olfactory bulb and improves odor memory. J Neurosci. 22, 2679-89.
4. Doetsch, F., Caille, I., Lim, D. A., Garcia-Verdugo, J. M., Alvarez-Buylla, A., 1999. Subventricular zone astrocytes are neural stem cells in the adult mammalian brain. Cell. 97, 703-16.
5. O'Sullivan, S. S., Johnson, M., Williams, D. R., Revesz, T., Holton, J. L., Lees, A. J., Perry, E. K., 2011. The effect of drug treatment on neurogenesis in Parkinson's disease. Mov. Disord. 26, 45-50.
6. Hancock, D.B., Martin, E.R., Staijch, J.M., Jewett, R., Stacy, M.A., Scout, B.L. 2007. Smoking, caffeine, and nonsteroidal anti-inflammatory drugs in families with Parkinson's disease. Arch. Neurol. 64, 576-580.
7. Lim, S. Y., Fox, S. H., Lang, A. E., 2009. Overview of the extranigral aspects of Parkinson disease. Arch Neurol. 66, 167-72.
8. Doty, R. L., Singh, A., Tetrud, J., Langston, J. W., 1992a. Lack of major olfactory dysfunction in MPTP-induced parkinsonism. Ann Neurol. 32, 97-100.
9. Parrish-Aungst, S., Shipley, M. T., Erdelyi, F., Szabo, G., Puche, A. C., 2007. Quantitative analysis of neuronal diversity in the mouse olfactory bulb. J. Comp. Neurol. 501, 825-36.
10. Huisman, E., Uylings, H. B. M., Hoogland, P. V., 2008. Gender-related changes in increase of dopaminergic neurons in the olfactory bulb of Parkinson's disease patients. Mov. Disord. 23, 1407-1413.
11. Hong, D.P., Fink, A.L., Uversky, V.N., 2009. Smoking and Parkinson's disease: does nicotine affect alpha-synuclein fibrillation ? Biochim. Biophys. Acta. 1794, 282-290.
12. Sanchez-Andrade, G., Kendrick, K. M., 2009. The main olfactory system and social learning in mammals. Behav Brain Res. 200, 323-35.
13. Ono, K., Hirohata, M., Yamada, M., 2007. Anti-fibrillogenic and fibril-destabilizing activity of nicotine in vitro: implications for the prevention and therapeutics of Lewy body disease. Exp. Neurol. 205, 414-424.
14. Winner, B., Desplats, P., Hagl, C., Klucken, J., Aigner, R., Ploetz, S., Laemke, J., Karl, A., Aigner, L., Masliah, E., Buerger, E., Winkler, J., 2009. Dopamine receptor activation promotes adult neurogenesis in an acute Parkinson model. Exp. Neurol. 219, 543-552.
15. Depboylu, C., Maurer, L., Matusch, A., Hermanns, G., Windolph, A., Béhé, M., Oertel, W.H., Höglinger, G.U., 2013. Effects of long-term treatment with pramipexole or levodopa on presynaptic markers assessed by longitudinal 123 I FP-CIT SPECT and histochemistry. NeuroImage. 79, 191-200.
16. Ma, S. Y., Roytta, M., Rinne, J. O., Collan, Y., Rinne, U. K., 1997. Correlation between neuromorphometry in the substantia nigra and clinical features in Parkinson's disease using disector counts. J Neurol Sci. 151, 83-7.
17. Winner, B., Cooper-Kuhn, C. M., Aigner, R., Winkler, J., Kuhn, H. G., 2002. Long- term survival and cell death of newly generated neurons in the adult rat olfactory bulb. Eur. J. Neurosci. 16, 1681-1689.
18. van den Berge, S. A., van Strien, M. E., Korecka, J. A., Dijkstra, A. A., Sluijs, J. A., Kooijman, L., Eggers, R., De Filippis, L., Vescovi, A. L., Verhaagen, J., van de Berg, W. D., Hol, E. M., 2011. The proliferative capacity of the subventricular zone is maintained in the parkinsonian brain. Brain. 134, 3249- 63.
19. Winner, B., Couillard-Despres, S., Geyer, M., Aigner, R., Bogdahn, U., Aigner, L., Kuhn, H. G., Winkler, J., 2008. Dopaminergic lesion enhances growth factor- induced striatal neuroblast migration. J. Neuropathol. Exp. Neurol. 67, 105- 116.
20. Van Kampen, J. M., Hagg, T., Robertson, H. A., 2004. Induction of neurogenesis in the adult rat subventricular zone and neostriatum following dopamine D3 receptor stimulation. Eur. J. Neurosci. 19, 2377-87.
21. Kempermann, G., 2011. Seven principles in the regulation of adult neurogenesis. Eur J Neurosci. 33, 1018-24.
22. Rodriguez-Gaztelumendi, A., Rojo, M. L., Pazos, A., Diaz, A., 2009. Altered CB receptor-signaling in prefrontal cortex from an animal model of depression is reversed by chronic fluoxetine. J Neurochem. 108, 1423-33.
23. Imamura, K., Okayasu, N., Nagatsu, T., 2012. Cerebral blood flow and freezing of gait in Parkinson's disease. Acta Neurol Scand. 126, 210-8.
24. Quinn, N. P., Rossor, M. N., Marsden, C. D., 1987. Olfactory threshold in Parkinson's disease. J. Neurol. Neurosurg. Psychiatry. 50, 88-9.
25. Pakkenberg, B., Moller, A., Gundersen, H. J., Mouritzen Dam, A., Pakkenberg, H., 1991. The absolute number of nerve cells in substantia nigra in normal subjects and in patients with Parkinson's disease estimated with an unbiased stereological method. J Neurol Neurosurg Psychiatry. 54, 30-3.
26. Doty, R. L., Stern, M. B., Pfeiffer, C., Gollomp, S. M., Hurtig, H. I., 1992b. Bilateral olfactory dysfunction in early stage treated and untreated idiopathic Parkinson's disease. J. Neurol. Neurosurg. Psychiatry. 55, 138-42.
27. Marsden, C. D., 1990. Parkinson's disease. Lancet. 335, 948-52.
28. Nottebohm, F., 2004. The road we travelled: discovery, choreography, and significance of brain replaceable neurons. Ann N Y Acad Sci. 1016, 628-58.
29. Lo, S. E., Jain, S., 2006. Patient page. Slowing down a "slow" movement disorder: selegiline's benefit in treating Parkinson disease. Neurology. 66, E28-9.
30. Tanner, C.M., Goldman, S.M., Aston, D.A., Ottman, R., Ellenberg, J., Mayeux, R., 2002. Smoking and Parkinson's disease in twins. Neurology. 58, 581-588
31. Mandairon, N., Sultan, S., Nouvian, M., Sacquet, J., Didier, A., 2011. Involvement of newborn neurons in olfactory associative learning? The operant or non- operant component of the task makes all the difference. J Neurosci. 31, 12455- 60.
32. Mouret, A., Lepousez, G., Gras, J., Gabellec, M.-M., Lledo, P.-M., 2009. Turnover of newborn olfactory bulb neurons optimizes olfaction. J. Neurosci. 29, 12302- 12314.
33. Marxreiter, F., Nuber, S., Kandasamy, M., Klucken, J., Aigner, R., Burgmayer, R., Couillard-Despres, S., Riess, O., Winkler, J., Winner, B., 2009. Changes in adult olfactory bulb neurogenesis in mice expressing the A30P mutant form of alpha-synuclein. Eur J Neurosci. 29, 879-90.
34. Gage, F. H., 2000. Mammalian neural stem cells. Science. 287, 1433-8.
35. Carleton, A., Rochefort, C., Morante-Oria, J., Desmaisons, D., Vincent, J. D., Gheusi, G., Lledo, P.-M., 2002. Making scents of olfactory neurogenesis. J. Physiol. Paris. 96, 115-22.
36. Parkinson, J., 2002. An essay on the shaking palsy. 1817. J Neuropsychiatry Clin Neurosci. 14, 223-36.
37. Deumens, R., Blokland, A., Prickaerts, J., 2002. Modeling Parkinson's disease in rats: an evaluation of 6-OHDA lesions of the nigrostriatal pathway. Exp Neurol. 175, 303-17.
38. Dickson, D. W., Fujishiro, H., DelleDonne, A., Menke, J., Ahmed, Z., Klos, K. J., Josephs, K. A., Frigerio, R., Burnett, M., Parisi, J. E., Ahlskog, J. E., 2008. Evidence that incidental Lewy body disease is pre-symptomatic Parkinson's disease. Acta Neuropathol. 115, 437-44.
39. Ubeda-Bañon, I., Saiz-Sanchez, D., de la Rosa-Prieto, C., Argandoña-Palacios, L., Garcia-Muñozguren, S., Martinez-Marcos, A., 2010. alpha-Synucleinopathy in the human olfactory system in Parkinson's disease: involvement of calcium- binding protein-and substance P-positive cells. Acta neuropathologica. 119, 723-735.
40. Wirdefeldt, K., Adami, H. O., Cole, P., Trichopoulos, D., Mandel, J., 2011. Epidemiology and etiology of Parkinson's disease: a review of the evidence. Eur J Epidemiol. 26 Suppl 1, S1-58.
41. Roth, J., Radil, T., Ruzicka, E., Jech, R., Tichy, J., 1998. Apomorphine does not influence olfactory thresholds in Parkinson's disease. Funct. Neurol. 13, 99- 103.
42. Ross, G. W., Abbott, R. D., Petrovitch, H., Morens, D. M., Grandinetti, A., Tung, K. H., Tanner, C. M., Masaki, K. H., Blanchette, P. L., Curb, J. D., Popper, J. S., White, L. R., 2000. Association of coffee and caffeine intake with the risk of Parkinson disease. JAMA. 283, 2674-9.
43. Ross, G. W., Petrovitch, H., Abbott, R. D., Tanner, C. M., Popper, J., Masaki, K., Launer, L., White, L. R., 2008. Association of olfactory dysfunction with risk for future Parkinson's disease. Ann Neurol. 63, 167-73.
44. Witt, M., Bormann, K., Gudziol, V., Pehlke, K., Barth, K., Minovi, A., Hähner, A., Reichmann, H., Hummel, T., 2009. Biopsies of olfactory epithelium in patients with Parkinson's disease. Movement disorders : official journal of the Movement Disorder Society. 24, 906-914. References 82
45. Wachowiak, M., Shipley, M. T., 2006. Coding and synaptic processing of sensory information in the glomerular layer of the olfactory bulb. Seminars in cell & developmental biology. 17, 411-423.
46. Hsia, A. Y., Vincent, J. D., Lledo, P. M., 1999. Dopamine depresses synaptic inputs into the olfactory bulb. J. Neurophysiol. 82, 1082-1085.
47. O'Keeffe, G. C., Barker, R. A., Caldwell, M. A., 2009a. Dopaminergic modulation of neurogenesis in the subventricular zone of the adult brain. Cell Cycle. 8, 2888- 2894.
48. Freundlieb, N., Francois, C., Tande, D., Oertel, W. H., Hirsch, E. C., Hoglinger, G. U., 2006. Dopaminergic substantia nigra neurons project topographically organized to the subventricular zone and stimulate precursor cell proliferation in aged primates. J Neurosci. 26, 2321-5.
49. Shipley, M. T., Ennis, M., 1996. Functional organization of olfactory system. J Neurobiol. 30, 123-76.
50. Farrer, M. J., 2006. Genetics of Parkinson disease: paradigm shifts and future prospects. Nature Reviews Genetics. 7, 306-318.
51. Hirtz, D., Thurman, D. J., Gwinn-Hardy, K., Mohamed, M., Chaudhuri, A. R., Zalutsky, R., 2007. How common are the "common" neurologic disorders? Neurology. 68, 326-37.
52. Curtis, M. A., Kam, M., Nannmark, U., Anderson, M. F., Axell, M. Z., Wikkelso, C., Holtas, S., van Roon-Mom, W. M., Bjork-Eriksson, T., Nordborg, C., Frisen, J., Dragunow, M., Faull, R. L., Eriksson, P. S., 2007. Human neuroblasts migrate to the olfactory bulb via a lateral ventricular extension. Science. 315, 1243-9.
53. Kuhn, H. G., Biebl, M., Wilhelm, D., Li, M., Friedlander, R. M., Winkler, J., 2005. Increased generation of granule cells in adult Bcl-2-overexpressing mice: a role for cell death during continued hippocampal neurogenesis. Eur. J. Neurosci. 22, 1907-1915.
54. Lazarini, F., Lledo, P. M., 2011. Is adult neurogenesis essential for olfaction? Trends Neurosci. 34, 20-30.
55. Lois, C., Alvarez-Buylla, A., 1994. Long-distance neuronal migration in the adult mammalian brain. Science 264, 1145-1148.
56. Bronstein, J., Carvey, P., Chen, H., Cory-Slechta, D., DiMonte, D., Duda, J., English, P., Goldman, S., Grate, S., Hansen, J., Hoppin, J., Jewell, S., Kamel, F., Koroshetz, W., Langston, J. W., Logroscino, G., Nelson, L., Ravina, B., Rocca, W., Ross, G. W., Schettler, T., Schwarzschild, M., Scott, B., Seegal, R., Singleton, A., Steenland, K., Tanner, C. M., Van Den Eeden, S., Weisskopf, M., 2009. Meeting report: consensus statement-Parkinson's disease and the environment: collaborative on health and the environment and Parkinson's Action Network (CHE PAN) conference 26-28 June 2007. Environ Health Perspect. 117, 117-21.
57. Hirsch, E., Graybiel, A. M., Agid, Y. A., 1988. Melanized dopaminergic neurons are differentially susceptible to degeneration in Parkinson's disease. Nature. 334, 345-8.
58. Yasar, S., Justinova, Z., Lee, S.-H., Stefanski, R., Goldberg, S. R., Tanda, G., 2006. Metabolic transformation plays a primary role in the psychostimulant-like discriminative-stimulus effects of selegiline [(R)-(-)-deprenyl]. J. Pharmacol. Exp. Ther. 317, 387-394.
59. Rascol, O., Lozano, A., Stern, M., Poewe, W., 2011. Milestones in Parkinson's disease therapeutics. Mov Disord. 26, 1072-82.
60. Fernandez, H. H., Chen, J. J., 2007. Monamine oxidase inhibitors: current and emerging agents for Parkinson disease. Clin. Neuropharmacol. 30, 150-168. References 75
61. Yamada, M., Onodera, M., Mizuno, Y., Mochizuki, H., 2004. Neurogenesis in olfactory bulb identified by retroviral labeling in normal and 1-methyl-4- phenyl-1,2,3,6-tetrahydropyridine-treated adult mice. Neuroscience. 124, 173- 81.
62. Kaplan, M. S., Hinds, J. W., 1977. Neurogenesis in the adult rat: electron microscopic analysis of light radioautographs. Science. 197, 1092-4.
63. Kalaitzakis, M. E., Graeber, M. B., Gentleman, S. M., Pearce, R. K., 2009. Parkinson disease: extranigral, multisystem, and {alpha}-synuclein "plus". Arch Neurol. 66, 914-5; author reply 915-6.
64. Langston, J. W., Ballard, P. A., Jr., 1983. Parkinson's disease in a chemist working with 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine. N Engl J Med. 309, 310.
65. Prediger, R. D., Rial, D., Medeiros, R., Figueiredo, C. P., Doty, R. L., Takahashi, R. N., 2009. Risk is in the air: an intranasal MPTP (1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine) rat model of Parkinson's disease. Ann N Y Acad Sci. 1170, 629-36.
66. Imayoshi, I., Sakamoto, M., Ohtsuka, T., Takao, K., Miyakawa, T., Yamaguchi, M., Mori, K., Ikeda, T., Itohara, S., Kageyama, R., 2008. Roles of continuous References 76 neurogenesis in the structural and functional integrity of the adult forebrain. Nat. Neurosci. 11, 1153-1161.
67. Pålhagen, S., Heinonen, E. H., Hagglund, J., Kaugesaar, T., Kontants, H., Maki-Ikola, O., Palm, R., Turunen, J., 1998. Selegiline delays the onset of disability in de novo parkinsonian patients. Swedish Parkinson Study Group. Neurology. 51, 520-5.
68. Pålhagen, S., Heinonen, E., Hagglund, J., Kaugesaar, T., Maki-Ikola, O., Palm, R., 2006. Selegiline slows the progression of the symptoms of Parkinson disease. Neurology. 66, 1200-6.
69. Buck, L. B., Smell and Taste: The Chemical Senses. In: E. Kandel, et al., 4th Eds. Principles of Neural Science. McGraw-Hill Medical, New York, 2000, pp. 625-36.
70. Song, C., Leonard, B. E., 2005. The olfactory bulbectomised rat as a model of depression. Neurosci Biobehav Rev. 29, 627-47.
71. Poewe, W., 2009. Treatments for Parkinson disease--past achievements and current clinical needs. Neurology. 72, S65-73.
72. Kirik, D., Rosenblad, C., Bjorklund, A., 1998. Characterization of behavioral and neurodegenerative changes following partial lesions of the nigrostriatal dopamine system induced by intrastriatal 6-hydroxydopamine in the rat. Exp Neurol. 152, 259-77.
73. Liu, Z., Martin, L. J., 2003. Olfactory bulb core is a rich source of neural progenitor and stem cells in adult rodent and human. J. Comp. Neurol. 459, 368-91.
74. Huisman, E., Uylings, H. B. M., Hoogland, P. V., 2004. A 100% increase of dopaminergic cells in the olfactory bulb may explain hyposmia in Parkinson's disease. Mov. Disord. 19, 687-692.
75. Fahn, S., 2008. The history of dopamine and levodopa in the treatment of Parkinson's disease. Mov Disord. 23 Suppl 3, S497-508.
76. Lang, A. E., 2011. A critical appraisal of the premotor symptoms of Parkinson's disease: potential usefulness in early diagnosis and design of neuroprotective trials. Mov Disord. 26, 775-83.
77. Fleming, S. M., Tetreault, N. A., Mulligan, C. K., Hutson, C. B., Masliah, E., Chesselet, M. F., 2008. Olfactory deficits in mice overexpressing human wildtype alpha-synuclein. Eur J Neurosci. 28, 247-56.
78. Systemic administration of neuregulin-1beta1 protects dopaminergic neurons in a mouse model of Parkinson's disease. J Neurochem. 117, 1066-74.
79. Spillantini, M. G., Schmidt, M. L., Lee, V. M., Trojanowski, J. Q., Jakes, R., Goedert, M., 1997. Alpha-synuclein in Lewy bodies. Nature. 388, 839-40.
80. Höglinger, G. U., Rizk, P., Muriel, M. P., Duyckaerts, C., Oertel, W. H., Caille, I., Hirsch, E. C., 2004. Dopamine depletion impairs precursor cell proliferation in Parkinson disease. Nat. Neurosci. 7, 726-735.
81. Ries, V., Henchcliffe, C., Kareva, T., Rzhetskaya, M., Bland, R., During, M. J., Kholodilov, N., Burke, R. E., 2006. Oncoprotein Akt/PKB induces trophic effects in murine models of Parkinson's disease. Proc. Natl. Acad. Sci. USA. 103, 18757-62.
82. Tian, C., Murrin, L. C., Zheng, J. C., 2009. Mitochondrial fragmentation is involved in methamphetamine-induced cell death in rat hippocampal neural progenitor cells. PLoS One. 4, e5546.
83. O'Keeffe, G. C., Tyers, P., Aarsland, D., Dalley, J. W., Barker, R. A., Caldwell, M. A., 2009b. Dopamine-induced proliferation of adult neural precursor cells in the mammalian subventricular zone is mediated through EGF. Proc. Natl. Acad. Sci. USA. 106, 8754-8759.
84. Lazarini, F., Mouthon, M.-A., Gheusi, G., de Chaumont, F., Olivo-Marin, J.-C., Lamarque, S., Abrous, D. N., Boussin, F. D., Lledo, P.-M., 2009. Cellular and behavioral effects of cranial irradiation of the subventricular zone in adult mice. PLoS ONE. 4, e7017. References 77
85. Lindvall, O., Kokaia, Z., 2010. Stem cells in human neurodegenerative disorders-- time for clinical translation? J Clin Invest. 120, 29-40.
86. Suh, H., Deng, W., Gage, F. H., 2009. Signaling in adult neurogenesis. Annu Rev Cell Dev Biol. 25, 253-75.
87. Jaskelioff, M., Muller, F. L., Paik, J.-H., Thomas, E., Jiang, S., Adams, A. C., Sahin, E., Kost-Alimova, M., Protopopov, A., Cadiñanos, J., Horner, J. W., Maratos- Flier, E., Depinho, R. A., 2011. Telomerase reactivation reverses tissue degeneration in aged telomerase-deficient mice. Nature. 469, 102-106.
88. Young, S. Z., Taylor, M. M., Bordey, A., 2011. Neurotransmitters couple brain activity to subventricular zone neurogenesis. Eur J Neurosci. 33, 1123-32.
89. Masayuki Sakamoto, I. I. T. O. M. Y. K. M. a. R. K., 2011. Continuous neurogenesis in the adult forebrain is required for innate olfactory responses. PNAS. 1-6.
90. Riederer, P., Laux, G., 2011. MAO-inhibitors in Parkinson's Disease. Exp Neurobiol. 20, 1-17.
91. Sui, Y., Horne, M. K., Stanic, D., 2012. Reduced proliferation in the adult mouse subventricular zone increases survival of olfactory bulb interneurons. PLoS One. 7, e31549.
92. Brill, M. S., Snapyan, M., Wohlfrom, H., Ninkovic, J., Jawerka, M., Mastick, G. S., Ashery-Padan, R., Saghatelyan, A., Berninger, B., Gotz, M., 2008. A dlx2- and pax6-dependent transcriptional code for periglomerular neuron specification in the adult olfactory bulb. J Neurosci. 28, 6439-52.
93. The Parkinson Study Group, 1993. Effects of tocopherol and deprenyl on the progression of disability in early Parkinson's disease. The Parkinson Study Group. N. Engl. J. Med. 328, 176-83.
94. Ungerstedt, U., 1968. 6-Hydroxy-dopamine induced degeneration of central monoamine neurons. Eur J Pharmacol. 5, 107-10.
95. Schwarzschild, M. A., Agnati, L., Fuxe, K., Chen, J. F., Morelli, M., 2006. Targeting adenosine A2A receptors in Parkinson's disease. Trends Neurosci. 29, 647-54.
96. Tillerson, J. L., Caudle, W. M., Parent, J. M., Gong, C., Schallert, T., Miller, G. W., 2006. Olfactory discrimination deficits in mice lacking the dopamine transporter or the D2 dopamine receptor. Behav Brain Res. 172, 97-105. References 81
97. Tadaiesky, M. T., Dombrowski, P. A., Figueiredo, C. P., Cargnin-Ferreira, E., Da Cunha, C., Takahashi, R. N., 2008. Emotional, cognitive and neurochemical alterations in a premotor stage model of Parkinson's disease. Neuroscience. 156, 830-40.
98. Ming, G.-L. and Song, H., 2011. Adult neurogensis in the mammalian brain: Significant answers and significant questions. Neuron. 70, 687-702.
99. Polymeropoulos, M. H., Lavedan, C., Leroy, E., Ide, S. E., Dehejia, A., Dutra, A., Pike, B., Root, H., Rubenstein, J., Boyer, R., Stenroos, E. S., Chandrasekharappa, S., Athanassiadou, A., Papapetropoulos, T., Johnson, W. G., Lazzarini, A. M., Duvoisin, R. C., Di Iorio, G., Golbe, L. I., Nussbaum, R. L., 1997. Mutation in the alpha-synuclein gene identified in families with Parkinson's disease. Science. 276, 2045-7. References 79
100. Hack, M. A., Saghatelyan, A., de Chevigny, A., Pfeifer, A., Ashery-Padan, R., Lledo, P. M., Gotz, M., 2005. Neuronal fate determinants of adult olfactory bulb neurogenesis. Nat Neurosci. 8, 865-72.
101. Lledo, P.-M., Alonso, M., Grubb, M. S., 2006. Adult neurogenesis and functional plasticity in neuronal circuits. Nat. Rev. Neurosci. 7, 179-193.
102. Jenner, P., Langston, J. W., 2011. Explaining ADAGIO: a critical review of the biological basis for the clinical effects of rasagiline. Mov. Disord. 26, 2316- 23.
103. Taylor, T. N., Caudle, W. M., Shepherd, K. R., Noorian, A., Jackson, C. R., Iuvone, P. M., Weinshenker, D., Greene, J. G., Miller, G. W., 2009. Nonmotor symptoms of Parkinson's disease revealed in an animal model with reduced monoamine storage capacity. J Neurosci. 29, 8103-13.

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