Parkinson’s disease: Animal models and dopaminergic cell vulnerability

Frontiers in Neuroanatomy

Volumn 8, Issue DEC, 2014, Pages

  Blesa, Javier ^a   Przedborski, Serge ^a  

^a Columbia University ^*  (United States)

Author keywords

6 OHDA; ATP13A2; DJ1; LRRK2; MPTP; Parkin; Rotenone; Synuclein

Indexed keywords

1,2,3,6 TETRAHYDRO 1 METHYL 4 PHENYLPYRIDINE; ADENOSINE TRIPHOSPHATASE; ADENOSINE TRIPHOSPHATASE 13A2; ALPHA SYNUCLEIN; AUTOPHAGY PROTEIN 7; DJ 1 PROTEIN; ENGRAILED 1 PROTEIN; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; LEUCINE RICH REPEAT KINASE 2; MANEB; NUCLEAR RECEPTOR RELATED FACTOR 1; OXIDOPAMINE; PARAQUAT; PARKIN; PEPTIDES AND PROTEINS; PSYCHOSTIMULANT AGENT; ROTENONE; SONIC HEDGEHOG PROTEIN; TRANSCRIPTION FACTOR PITX3; UNCLASSIFIED DRUG; VESICULAR MONOAMINE TRANSPORTER 2;

ANIMAL BEHAVIOR; ANIMAL MODEL; ARTICLE; CELL LOSS; CORPUS STRIATUM; DISEASE MODEL; DOPAMINE METABOLISM; DOPAMINERGIC NERVE CELL; DOPAMINERGIC SYSTEM; EXPERIMENTAL BEHAVIORAL TEST; GENE MUTATION; GENETIC MODEL; HUMAN; MOTOR CONTROL; MOTOR DYSFUNCTION; MOTOR PERFORMANCE; NERVE DEGENERATION; NEUROPATHOLOGY; NEUROTOXICITY; NIGRONEOSTRIATAL SYSTEM; NONHUMAN; PARKINSON DISEASE; SUBSTANTIA NIGRA PARS COMPACTA; TRANSGENIC MOUSE;

EID: 84918784944     PISSN: None     EISSN: 16625129     Source Type: Journal    
DOI: 10.3389/fnana.2014.00155     Document Type: Article

References (202)

1. Akundi, R. S., Huang, Z., Eason, J., Pandya, J. D., Zhi, L., Cass, W. A., et al. (2011). Increased mitochondrial calcium sensitivity and abnormal expression of innate immunity genes precede dopaminergic defects in Pink1-deficient mice. PLoS ONE6:e16038. doi: 10.1371/journal.pone.0016038
2. Alam, M., Mayerhofer, A., and Schmidt, W. J. (2004). The neurobehavioral changes induced by bilateral rotenone lesion in medial forebrain bundle of rats are reversed by L-DOPA. Behav. Brain Res.151, 117–124. doi: 10.1016/j.bbr.2003.08.014
3. Andres-Mateos, E., Perier, C., Zhang, L., Blanchard-Fillion, B., Greco, T. M., Thomas, B., et al. (2007). DJ-1 gene deletion reveals that DJ-1 is an atypical peroxiredoxin-like peroxidase. Proc. Natl. Acad. Sci. U.S.A.104, 14807–14812. doi: 10.1073/pnas.0703219104
4. Baiguera, C., Alghisi, M., Pinna, A., Bellucci, A., De Luca, M. A., Frau, L., et al. (2012). Late-onset Parkinsonism in NFκB/c-Rel-deficient mice. Brain135, 2750–2765. doi: 10.1093/brain/aws193
5. Baptista, M. A. S., Dave, K. D., Frasier, M. A., Sherer, T. B., Greeley, M., Beck, M. J., et al. (2013). Loss of leucine-rich repeat kinase 2 (LRRK2) in rats leads to progressive abnormal phenotypes in peripheral organs. PLoS ONE8:e80705. doi: 10.1371/journal.pone.0080705
6. Bastías-Candia, S., Di Benedetto, M., D’Addario, C., Candeletti, S., and Romualdi, P. (2013). Combined exposure to agriculture pesticides, paraquat and maneb, induces alterations in the N/OFQ-NOPr and PDYN/KOPr systems in rats: relevance to sporadic Parkinson’s disease. Environ. Toxicol. doi: 10.1002/tox.21943 [Epub ahead of print].
7. Berg, J., Roch, M., Altschüler, J., Winter, C., Schwerk, A., Kurtz, A., et al. (2014). Human adipose-derived mesenchymal stem cells improve motor functions and are neuroprotective in the 6-hydroxydopamine-rat model for parkinson’s disease when cultured in monolayer cultures but suppress hippocampal neurogenesis and hippocampal memory functi. Stem Cell Rev. Rep. doi: 10.1007/s12015-014-9551-y [Epub ahead of print].
8. Berry, C., La Vecchia, C., and Nicotera, P. (2010). Paraquat and Parkinson’s disease. Cell Death Differ. 17, 1115–1125. doi: 10.1038/cdd.2009.217
9. Betarbet, R., Sherer, T. B., MacKenzie, G., Garcia-Osuna, M., Panov, A. V., and Greenamyre, J. T. (2000). Chronic systemic pesticide exposure reproduces features of Parkinson’s disease. Nat. Neurosci.3, 1301–1306. doi: 10.1038/81834
10. Bezard, E., Imbert, C., Deloire, X., Bioulac, B., and Gross, C. E. (1997). A chronic MPTP model reproducing the slow evolution of Parkinson’s disease: evolution of motor symptoms in the monkey. Brain Res. 766, 107–112. doi: 10.1016/S0006-8993(97)00531-3
11. Blandini, F., Armentero, M.-T., and Martignoni, E. (2008). The 6-hydroxydopamine model: news from the past. Parkinsonism Relat. Disord.14(Suppl. 2), S124–S129. doi: 10.1016/j.parkreldis.2008.04.015
12. Blesa, J., Juri, C., Collantes, M., Peñuelas, I., Prieto, E., Iglesias, E., et al. (2010). Progression of dopaminergic depletion in a model of MPTP-induced Parkin-sonism in non-human primates. An (18)F-DOPA and (11)C-DTBZ PET study. Neurobiol. Dis. 38, 456–463. doi: 10.1016/j.nbd.2010.03.006
13. Blesa, J., Juri, C., Garcia-Cabezas, M. A., Adanez, R., Sanchez-Gonzalez, M. A., Cavada, C., et al. (2011). Inter-hemispheric asymmetry of nigrostriatal dopamin-ergic lesion: a possible compensatory mechanism in Parkinson’s disease. Front. Syst. Neurosci.5:92. doi: 10.3389/fnsys.2011.00092
14. Blesa, J., Pifl, C., Sánchez-González, M. A., Juri, C., García-Cabezas, M. A., Adánez, R., et al. (2012). The nigrostriatal systeminthe presymptomatic and symptomatic stages in the MPTP monkey model: a PET, histological and biochemical study. Neurobiol. Dis.48, 79–91. doi: 10.1016/j.nbd.2012.05.018
15. Brehm, N., Bez, F., Carlsson, T., Kern, B., Gispert, S., Auburger, G., et al. (2014). A genetic mouse model of Parkinson’s disease shows involuntary movements and increased postsynaptic sensitivity to apomorphine. Mol. Neurobiol. doi: 10.1007/s12035-014-8911–8916 [Epub ahead of print].
16. Brichta, L., Greengard, P., and Flajolet, M. (2013). Advances in the pharmacological treatment of Parkinson’s disease: targeting neurotransmitter systems. Trends Neurosci. 36, 543–554. doi: 10.1016/j.tins.2013.06.003
17. Brooks, A. I., Chadwick, C. A., Gelbard, H. A., Cory-Slechta, D. A., and Federoff, H. J. (1999). Paraquat elicited neurobehavioral syndrome caused by dopaminergic neuron loss. Brain Res. 823, 1–10. doi: 10.1016/S0006-8993(98)01192-5
18. Cadet, J. L., Krasnova, I. N., Jayanthi, S., and Lyles, J. (2007). Neurotoxicity of substituted amphetamines: molecular and cellular mechanisms. Neurotox. Res.11, 183–202. doi: 10.1007/BF03033567
19. Campos, F. L., Carvalho, M. M., Cristovão, A. C., Je, G., Baltazar, G., Salgado, A. J., et al. (2013). Rodent models of Parkinson’s disease: beyond the motor symptomatology. Front. Behav. Neurosci.7:175. doi: 10.3389/fnbeh.2013.00175
20. Cannon, J. R., Tapias, V., Na, H. M., Honick, A. S., Drolet, R. E., and Greenamyre, J. T. (2009). A highly reproducible rotenone model of Parkinson’s disease. Neurobiol. Dis.34, 279–290.
21. Capela, J. P., Carmo, H., Remião, F., Bastos, M. L., Meisel, A., and Carvalho, F. (2009). Molecular and cellular mechanisms of ecstasy-induced neurotoxicity: an overview. Mol. Neurobiol. 39, 210–271. doi: 10.1007/s12035-009-8064–8061
22. Chege, P. M., and McColl, G. (2014). Caenorhabditis elegans: a model to investigate oxidative stress and metal dyshomeostasis in Parkinson’s disease. Front. Aging Neurosci. 6:89. doi: 10.3389/fnagi.2014.00089
23. Chen, C.-Y., Weng, Y.-H., Chien, K.-Y., Lin, K.-J., Yeh, T.-H., Cheng, Y.-P., et al. (2012). (G2019S) LRRK2 activates MKK4-JNK pathway and causes degeneration of SN dopaminergic neurons in a transgenic mouse model of PD. Cell Death Differ. 19, 1623–1633. doi: 10.1038/cdd.2012.42
24. Chen, L., Thiruchelvam, M. J., Madura, K., and Richfield, E. K. (2006). Proteasome dysfunction in aged human alpha-synuclein transgenic mice. Neurobiol. Dis.23, 120–126. doi: 10.1016/j.nbd.2006.02.004
25. Chiueh, C. C., Markey, S. P., Burns, R. S., Johannessen, J. N., Jacobowitz, D. M., and Kopin, I. J. (1984). Neurochemical and behavioral effects of 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP) in rat, guinea pig, and monkey. Psychopharmacol. Bull. 20, 548–553.
26. Costa, G., Frau, L., Wardas, J., Pinna, A., Plumitallo, A., and Morelli, M. (2013). MPTP-induced dopamine neuron degeneration and glia activation is potentiated in MDMA-pretreated mice. Mov. Disord.28, 1957–1965. doi: 10.1002/mds.25646
27. Dantuma, N. P., and Bott, L. C. (2014). The ubiquitin-proteasome system in neu-rodegenerative diseases: precipitating factor, yet part of the solution. Front. Mol. Neurosci.7:70. doi: 10.3389/fnmol.2014.00070
28. Dauer, W., Kholodilov, N., Vila, M., Trillat, A.-C. C., Goodchild, R., Larsen, K. E., et al. (2002). Resistance of alpha -synuclein null mice to the parkin-sonian neurotoxin MPTP. Proc. Natl. Acad. Sci. U.S.A.99, 14524–14529. doi: 10.1073/pnas.172514599
29. Dauer, W., and Przedborski, S. (2003). Parkinson’s disease: mechanisms and models. Neuron39, 889–909. doi: 10.1016/S0896-6273(03)00568-3
30. Dawson, T. M., Ko, H. S., and Dawson, V. L. (2010). Genetic animal models of Parkinson’s disease. Neuron66, 646–661. doi: 10.1016/j.neuron.2010.04.034
31. Day, B. J., Patel, M., Calavetta, L., Chang, L. Y., and Stamler, J. S. (1999). A mechanism of paraquat toxicity involving nitric oxide synthase. Proc. Natl. Acad. Sci. U.S.A.96, 12760–12765. doi: 10.1073/pnas.96.22.12760
32. Decressac, M., Mattsson, B., Lundblad, M., Weikop, P., and Björklund, A. (2012). Progressive neurodegenerative and behavioural changes induced by AAV-mediated overexpression of α-synuclein in midbrain dopamine neurons. Neurobiol. Dis.45, 939–953. doi: 10.1016/j.nbd.2011.12.013
33. Dong, Z., Ferger, B., Feldon, J., and Büeler, H. (2002). Overexpression of Parkinson’s disease-associated alpha-synucleinA53T by recombinant adeno-associated virus in mice does not increase the vulnerability of dopaminergic neurons to MPTP. J. Neurobiol.53, 1–10. doi: 10.1002/neu.10094
34. Drui, G., Carnicella, S., Carcenac, C., Favier, M., Bertrand, A., Boulet, S., et al. (2014). Loss of dopaminergic nigrostriatal neurons accounts for the motivational and affective deficits in Parkinson’s disease. Mol. Psychiatry19, 358–367. doi: 10.1038/mp.2013.3
35. Dunnett, S. B., and Lelos, M. (2010). Behavioral analysis of motor and non-motor symptoms in rodent models of Parkinson’s disease. Prog. Brain Res.184, 35–51. doi: 10.1016/S0079-6123(10)840038
36. Dusonchet, J., Kochubey, O., Stafa, K., Young, S. M., Zufferey, R., Moore, D. J., et al. (2011). A rat model of progressive nigral neurodegeneration induced by the Parkinson’s disease-associated G2019S mutation in LRRK2. J. Neurosci.31, 907–912. doi: 10.1523/JNEUROSCI.5092-10.2011
37. Ekstrand, M. I., Terzioglu, M., Galter, D., Zhu, S., Hofstetter, C., Lindqvist, E., et al. (2007). Progressive parkinsonism in mice with respiratory-chain-deficient dopamine neurons. Proc. Natl. Acad. Sci. U.S.A.104, 1325–1330. doi: 10.1073/pnas.0605208103
38. El Ayadi, A., and Zigmond, M. J. (2011). Low concentrations of methamphetamine can protect dopaminergic cells against a larger oxidative stress injury: mechanistic study. PLoS ONE6:e24722. doi: 10.1371/journal.pone.0024722
39. Exner, N., Lutz, A. K., Haass, C., and Winklhofer, K. F. (2012). Mitochondrial dysfunction in Parkinson’s disease: molecular mechanisms and pathophysiological consequences. EMBO J. 31, 3038–3062. doi: 10.1038/emboj.2012.170
40. Fleming, S. M., Zhu, C., Fernagut, P.-O., Mehta, A., DiCarlo, C. D., Seaman, R. L., et al. (2004). Behavioral and immunohistochemical effects of chronic intravenous and subcutaneous infusions of varying doses of rotenone. Exp. Neurol.187, 418–429. doi: 10.1016/j.expneurol.2004.01.023
41. Forno, L. S., Langston, J. W., DeLanney, L. E., Irwin, I., and Ricaurte, G. A. (1986). Locus ceruleus lesions and eosinophilic inclusions in MPTP-treated monkeys. Ann. Neurol.20, 449–455. doi: 10.1002/ana.410200403
42. Freire, C., and Koifman, S. (2012). Pesticide exposure and Parkinson’s disease: epidemiological evidence of association. Neurotoxicology33, 947–971. doi: 10.1016/j.neuro.2012.05.011
43. Friedman, L. G., Lachenmayer, M. L., Wang, J., He, L., Poulose, S. M., Komatsu, M., et al. (2012). Disrupted autophagy leads to dopaminergic axon and dendrite degeneration and promotes presynaptic accumulation of α-synuclein and LRRK2 in the brain. J. Neurosci.32, 7585–7593. doi: 10.1523/JNEUROSCI.5809-11.2012
44. Gandhi, S., Wood-Kaczmar, A., Yao, Z., Plun-Favreau, H., Deas, E., Klupsch, K., et al. (2009). PINK1-associated Parkinson’s disease is caused by neu-ronal vulnerability to calcium-induced cell death. Mol. Cell33, 627–638. doi: 10.1016/j.molcel.2009.02.013
45. Gautier, C. A., Kitada, T., and Shen, J. (2008). Loss of PINK1 causes mitochondrial functional defects and increased sensitivity to oxidative stress. Proc. Natl. Acad. Sci. U.S.A.105, 11364–11369. doi: 10.1073/pnas.0802076105
46. Giasson, B. I., Duda, J. E., Quinn, S. M., Zhang, B., Trojanowski, J. Q., and Lee, V. M. (2002). Neuronal alpha-synucleinopathy with severe movement disorder in mice expressing A53T human alpha-synuclein. Neuron34, 521–533. doi: 10.1016/S0896-6273(02)00682-7
47. Gispert, S., Del Turco, D., Garrett, L., Chen, A., Bernard, D. J., Hamm-Clement, J., et al. (2003). Transgenic mice expressing mutant A53T human alpha-synuclein show neuronal dysfunction in the absence of aggregate formation. Mol. Cell. Neurosci.24, 419–429. doi: 10.1016/S1044-7431(03)00198-2
48. Gispert, S., Ricciardi, F., Kurz, A., Azizov, M., Hoepken, H.-H., Becker, D., et al. (2009). Parkinson phenotype in aged PINK1-deficient mice is accompanied by progressive mitochondrial dysfunction in absence of neurodegeneration. PLoS ONE4:e5777. doi: 10.1371/journal.pone.0005777
49. Glajch, K. E., Fleming, S. M., Surmeier, D. J., and Osten, P. (2012). Sensorimotor assessment of the unilateral 6-hydroxydopamine mouse model of Parkinson’s disease. Behav. Brain Res.230, 309–316. doi: 10.1016/j.bbr.2011.12.007
50. Goedert, M., Spillantini, M. G., Del Tredici, K., and Braak, H. (2013). 100 years of Lewy pathology. Nat. Rev. Neurol. 9, 13–24. doi: 10.1038/nrneurol.2012.242
51. Goldberg, M. S., Fleming, S. M., Palacino, J. J., Cepeda, C., Lam, H. A., Bhat-nagar, A., et al. (2003). Parkin-deficient mice exhibit nigrostriatal deficits but not loss of dopaminergic neurons. J. Biol. Chem.278, 43628–43635. doi: 10.1074/jbc.M308947200
52. Goldberg, M. S., Pisani, A., Haburcak, M., Vortherms, T. A., Kitada, T., Costa, C., et al. (2005). Nigrostriatal dopaminergic deficits and hypokinesia caused by inactivation of the familial Parkinsonism-linked gene DJ-1. Neuron45, 489–496. doi: 10.1016/j.neuron.2005.01.041
53. Gomez-Isla, T., Irizarry, M. C., Mariash, A., Cheung, B., Soto, O., Schrump, S., et al. (2003). Motor dysfunction and gliosis with preserved dopaminergic markers in human alpha-synuclein A30P transgenic mice. Neurobiol. Aging24, 245–258. doi: 10.1016/S0197-4580(02)00091-X
54. Gonzalez-Reyes, L. E., Verbitsky, M., Blesa, J., Jackson-Lewis, V., Paredes, D., Tillack, K., et al. (2012). Sonic hedgehog maintains cellular and neurochem-ical homeostasis in the adult nigrostriatal circuit. Neuron75, 306–319. doi: 10.1016/j.neuron.2012.05.018
55. Good, C. H., Hoffman, A. F., Hoffer, B. J., Chefer, V. I., Shippenberg, T. S., Bäckman, C. M., et al. (2011). Impaired nigrostriatal function precedes behavioral deficits in a genetic mitochondrial model of Parkinson’s disease. FASEB J. 25, 1333–1344. doi: 10.1096/fj.10–173625
56. Granado, N., Escobedo, I., O’Shea, E., Colado, I., and Moratalla, R. (2008a). Early loss of dopaminergic terminals in striosomes after MDMA administration to mice. Synapse62, 80–84. doi: 10.1002/syn.20466
57. Granado, N., O’Shea, E., Bove, J., Vila, M., Colado, M. I., and Moratalla, R. (2008b). Persistent MDMA-induced dopaminergic neurotoxicity in the striatum and substantia nigra of mice. J. Neurochem.107, 1102–1112. doi: 10.1111/j.1471-4159.2008.05705.x
58. Guo, M. (2012). Drosophila as a model to study mitochondrial dysfunction in Parkinson’s disease. Cold Spring Harb. Perspect. Med. 2, pii:a009944. doi: 10.1101/cshperspect.a009944
59. Halliday, G., Herrero, M. T., Murphy, K., McCann, H., Ros-Bernal, F., Barcia, C., et al. (2009). No Lewy pathology in monkeys with over 10 years of severe MPTP Parkinsonism. Mov. Disord.24, 1519–1523. doi: 10.1002/mds.22481
60. Haque, M. E., Mount, M. P., Safarpour, F., Abdel-Messih, E., Callaghan, S., Mazerolle, C., et al. (2012). Inactivation of Pink1 gene in vivo sensitizes dopamine-producing neurons to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and can be rescued by autosomal recessive Parkinson disease genes, Parkin or DJ-1. J. Biol. Chem.287, 23162–23170. doi: 10.1074/jbc.M112.346437
61. Healy, D. G., Falchi, M., O’Sullivan, S. S., Bonifati, V., Durr, A., Bressman, S., et al. (2008). Phenotype, genotype, and worldwide genetic penetrance of LRRK2-associated Parkinson’s disease: a case-control study. Lancet. Neurol. 7, 583–590. doi: 10.1016/S1474-4422(08)70117–70110
62. Heinzen, E. L., Arzimanoglou, A., Brashear, A., Clapcote, S. J., Gurrieri, F., Goldstein, D. B., et al. (2014). Distinct neurological disorders with ATP1A3 mutations. Lancet. Neurol. 13, 503–514. doi: 10.1016/S1474-4422(14)70011–70010
63. Hennis, M. R., Marvin, M. A., Taylor, C. M., and Goldberg, M. S. (2014). Surprising behavioral and neurochemical enhancements in mice with combined mutations linked to Parkinson’s disease. Neurobiol. Dis.62, 113–123. doi: 10.1016/j.nbd.2013.09.009
64. Hennis, M. R., Seamans, K. W., Marvin, M. A., Casey, B. H., and Goldberg, M. S. (2013). Behavioral and neurotransmitter abnormalities in mice deficient for Parkin, DJ-1 and superoxide dismutase. PLoS ONE8:e84894. doi: 10.1371/journal.pone.0084894
65. Herzig, M. C., Kolly, C., Persohn, E., Theil, D., Schweizer, T., Hafner, T., et al. (2011). LRRK2 protein levels are determined by kinase function and are crucial for kidney and lung homeostasis in mice. Hum. Mol. Genet.20, 4209–4223. doi: 10.1093/hmg/ddr348
66. Hess, A., Desiderio, C., and McAuliffe, W. G. (1990). Acute neuropatho-logical changes in the caudate nucleus caused by MPTP and metham-phetamine: immunohistochemical studies. J. Neurocytol. 19, 338–342. doi: 10.1007/BF01188403
67. Hinkle, K. M., Yue, M., Behrouz, B., Dächsel, J. C., Lincoln, S. J., Bowles, E. E., et al. (2012). LRRK2 knockout mice have an intact dopaminergic system but display alterations in exploratory and motor co-ordination behaviors. Mol. Neurodegener.7:25. doi: 10.1186/1750-1326-725
68. Howard, C. D., Keefe, K. A., Garris, P. A., and Daberkow, D. P. (2011). Methamphetamine neurotoxicity decreases phasic, but not tonic, dopaminergic signaling in the rat striatum. J. Neurochem.118, 668–676. doi: 10.1111/j.1471-4159.2011.07342.x
69. Hwang, D.-Y., Ardayfio, P., Kang, U. J., Semina, E. V, and Kim, K.-S. (2003). Selective loss of dopaminergic neurons in the substantia nigra of Pitx3-deficient aphakia mice. Brain Res. Mol. Brain Res. 114, 123–131. doi: 10.1016/S0169-328X(03)00162-1
70. Ikeda, M., Kawarabayashi, T., Harigaya, Y., Sasaki, A., Yamada, S., Matsubara, E., et al. (2009). Motor impairment and aberrant production of neuro-chemicals in human alpha-synuclein A30P+A53T transgenic mice with alpha-synuclein pathology. Brain Res. 1250, 232–241. doi: 10.1016/j.brainres.2008.10.011
71. Itier, J.-M., Ibanez, P., Mena, M. A., Abbas, N., Cohen-Salmon, C., Bohme, G. A., et al. (2003). Parkin gene inactivation alters behaviour and dopamine neurotransmission in the mouse. Hum. Mol. Genet.12, 2277–2291. doi: 10.1093/hmg/ddg239
72. Jackson-Lewis, V., and Przedborski, S. (2007). Protocol for the MPTP mouse model of Parkinson’s disease. Nat. Protoc.2, 141–151. doi: 10.1038/nprot.2006.342
73. Janezic, S., Threlfell, S., Dodson, P. D., Dowie, M. J., Taylor, T. N., Potgieter, D., et al. (2013). Deficits in dopaminergic transmission precede neuron loss and dysfunction in a new Parkinson model. Proc. Natl. Acad. Sci. U.S.A.110, E4016–E4025. doi: 10.1073/pnas.1309143110
74. Jankovic, J., Chen, S., and Le, W. D. (2005). The role of Nurr1 in the development of dopaminergic neurons and Parkinson’s disease. Prog. Neurobiol. 77, 128–138. doi: 10.1016/j.pneurobio.2005.09.001
75. Jensen, K. F., Olin, J., Haykal-Coates, N., O’Callaghan, J., Miller, D. B., and de Olmos, J. S. (1993). Mapping toxicant-induced nervous system damage with a cupric silver stain: a quantitative analysis of neural degeneration induced by 3,4-methylenedioxymethamphetamine. NIDA Res. Monogr. 136, 133–149; discussion 150–154.
76. Jiang, C., Wan, X., He, Y., Pan, T., Jankovic, J., and Le, W. (2005). Age-dependent dopaminergic dysfunction in Nurr1 knockout mice. Exp. Neurol.191, 154–162. doi: 10.1016/j.expneurol.2004.08.035
77. Joselin, A. P., Hewitt, S. J., Callaghan, S. M., Kim, R. H., Chung, Y.-H., Mak, T. W., et al. (2012). ROS-dependent regulation of Parkin and DJ-1 localization during oxidative stress in neurons. Hum. Mol. Genet.21, 4888–4903. doi: 10.1093/hmg/dds325
78. Kadkhodaei, B., Ito, T., Joodmardi, E., Mattsson, B., Rouillard, C., Carta, M., et al. (2009). Nurr1 is required for maintenance of maturing and adult midbrain dopamine neurons. J. Neurosci. 29, 15923–15932. doi: 10.1523/JNEUROSCI.3910-09.2009
79. Kara, E., Kiely, A. P., Proukakis, C., Giffin, N., Love, S., Hehir, J., et al. (2014). A 6.4 Mb duplication of the α-synuclein locus causing frontotemporal dementia and parkinsonism: phenotype-genotype correlations.JAMA Neurol. 71, 1162–1171. doi: 10.1001/jamaneurol.2014.994
80. Kim, R. H., Smith, P. D., Aleyasin, H., Hayley, S., Mount, M. P., Pownall, S., et al. (2005). Hypersensitivity of DJ-1-deficient mice to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrindine (MPTP) and oxidative stress. Proc. Natl. Acad. Sci. U.S.A.102, 5215–5220. doi: 10.1073/pnas.0501282102
81. Kirik, D., Annett, L. E., Burger, C., Muzyczka, N., Mandel, R. J., and Björk-lund, A. (2003). Nigrostriatal alpha-synucleinopathy induced by viral vector-mediated overexpression of human alpha-synuclein: a new primate model of Parkinson’s disease. Proc. Natl. Acad. Sci. U.S.A.100, 2884–2889. doi: 10.1073/pnas.0536383100
82. Kirik, D., Rosenblad, C., Burger, C., Lundberg, C., Johansen, T. E., Muzy-czka, N., et al. (2002). Parkinson-like neurodegeneration induced by targeted overexpression of alpha-synuclein in the nigrostriatal system. J. Neurosci.22, 2780–2791.
83. Kitada, T., Pisani, A., Karouani, M., Haburcak, M., Martella, G., Tscherter, A., et al. (2009a). Impaired dopamine release and synaptic plasticity in the striatum of parkin-/- mice. J. Neurochem.110, 613–621. doi: 10.1111/j.1471-4159.2009.06152.x
84. Kitada, T., Tong, Y., Gautier, C. A., and Shen, J. (2009b). Absence of nigral degeneration in aged parkin/DJ-1/PINK1 triple knockout mice. J. Neurochem.111, 696–702. doi: 10.1111/j.1471-4159.2009.06350.x
85. Klein, R. L., King, M. A., Hamby, M. E., and Meyer, E. M. (2002). Dopamin-ergic cell loss induced by human A30P alpha-synuclein gene transfer to the rat substantia nigra. Hum. Gene Ther. 13, 605–612. doi: 10.1089/1043034025 2837206
86. Kogan, F. J., Nichols, W. K., and Gibb, J. W. (1976). Influence of methamphetamine on nigral and striatal tyrosine hydroxylase activity and on striatal dopamine levels. Eur. J. Pharmacol. 36, 363–371. doi: 10.1016/0014-2999(76)90090-X
87. Kowall, N. W., Hantraye, P., Brouillet, E., Beal, M. F., McKee, A. C., and Ferrante, R. J. (2000). MPTP induces alpha-synuclein aggregation in the substantia nigra of baboons. Neuroreport11, 211–213.
88. Lachenmayer, M. L., and Yue, Z. (2012). Genetic animal models for evaluating the role of autophagy in etiopathogenesis of Parkinson disease. Autophagy8, 1837–1838. doi: 10.4161/auto.21859
89. Lam, H. A., Wu, N., Cely, I., Kelly, R. L., Hean, S., Richter, F., et al. (2011). Elevated tonic extracellular dopamine concentration and altered dopamine modulation of synaptic activity precede dopamine loss in the striatum of mice overex-pressing human α-synuclein. J. Neurosci. Res.89, 1091–1102. doi: 10.1002/jnr.22611
90. Langston, J. W., Ballard, P., Tetrud, J. W., and Irwin, I. (1983). Chronic Parkinsonism inhumansduetoaproductofmeperidine-analogsynthesis. Science219, 979–980. doi: 10.1126/science.6823561
91. Lauwers, E., Bequé, D., Van Laere, K., Nuyts, J., Bormans, G., Mortel-mans, L., et al. (2007). Non-invasive imaging of neuropathology in a rat model of alpha-synuclein overexpression. Neurobiol. Aging28, 248–257. doi: 10.1016/j.neurobiolaging.2005.12.005
92. Lauwers, E., Debyser, Z., Van Dorpe, J., De Strooper, B., Nuttin, B., and Baekelandt, V. (2003). Neuropathology and neurodegeneration in rodent brain induced by lentiviral vector-mediated overexpression of alpha-synuclein. Brain Pathol. 13, 364–372. doi: 10.1111/j.1750-3639.2003.tb00035.x
93. Lee, B. D., Shin, J.-H., VanKampen, J., Petrucelli, L., West, A. B., Ko, H. S., et al. (2010). Inhibitors of leucine-rich repeat kinase-2 protect against models of Parkinson’s disease. Nat. Med.16, 998–1000. doi: 10.1038/nm.2199
94. Li, J., Dani, J. A., and Le, W. (2009a). The role of transcription factor Pitx3 in dopamine neuron development and Parkinson’s disease. Curr. Top. Med. Chem. 9, 855–859.
95. Li, Y., Liu, W., Oo, T. F., Wang, L., Tang, Y., Jackson-Lewis, V., et al. (2009b). Mutant LRRK2(R1441G) BAC transgenic mice recapitulate cardinal features of Parkinson’s disease. Nat. Neurosci.12, 826–828. doi: 10.1038/nn.2349
96. Li, X., Patel, J. C., Wang, J., Avshalumov, M. V., Nicholson, C., Buxbaum, J. D., et al. (2010). Enhanced striatal dopamine transmission and motor performance with LRRK2 overexpression in mice is eliminated by familial Parkinson’s disease mutation G2019S. J. Neurosci.30, 1788–1797. doi: 10.1523/JNEUROSCI.5604-09.2010
97. Lin, X., Parisiadou, L., Gu, X.-L., Wang, L., Shim, H., Sun, L., et al. (2009). Leucine-rich repeat kinase 2 regulates the progression of neuropathology induced by Parkinson’s-disease-related mutant alpha-synuclein. Neuron64, 807–827. doi: 10.1016/j.neuron.2009.11.006
98. Lin, X., Parisiadou, L., Sgobio, C., Liu, G., Yu, J., Sun, L., et al. (2012). Conditional expression of Parkinson’s disease-related mutant α-synuclein in the midbrain dopaminergic neurons causes progressive neurodegeneration and degradation of transcription factor nuclear receptor related 1. J. Neurosci.32, 9248–9264. doi: 10.1523/JNEUROSCI.1731-12.2012
99. Lo Bianco, C., Ridet, J.-L., Schneider, B. L., Deglon, N., and Aebischer, P. (2002). alpha -Synucleinopathy and selective dopaminergic neuron loss in a rat lentiviral-based model of Parkinson’s disease. Proc. Natl. Acad. Sci. U.S.A. 99, 10813–10818. doi: 10.1073/pnas.152339799
100. Lohr, K. M., Bernstein, A. I., Stout, K. A., Dunn, A. R., Lazo, C. R., Alter, S. P., et al. (2014). Increased vesicular monoamine transporter enhances dopamine release and opposes Parkinson disease-related neurodegeneration in vivo. Proc. Natl. Acad. Sci. U.S.A.111, 9977–9982. doi: 10.1073/pnas.1402134111
101. Lu, X.-H., Fleming, S. M., Meurers, B., Ackerson, L. C., Mortazavi, F., Lo, V., et al. (2009). Bacterial artificial chromosome transgenic mice expressing a truncated mutant parkin exhibit age-dependent hypokinetic motor deficits, dopaminergic neuron degeneration, and accumulation of proteinase K-resistant alpha-synuclein. J. Neurosci.29, 1962–1976. doi: 10.1523/JNEUROSCI.5351-08.2009
102. Lücking, C. B., Dürr, A., Bonifati, V., Vaughan, J., De Michele, G., Gasser, T., et al. (2000). Association between early-onset Parkinson’s disease and mutations in the parkin gene. N. Engl. J. Med. 342, 1560–1567. doi: 10.1056/NEJM200005253422103
103. Luk, K. C., Kehm, V., Carroll, J., Zhang, B., O’Brien, P., Trojanowski, J. Q., et al. (2012a). Pathological α-synuclein transmission initiates Parkinsonlike neurodegeneration in nontransgenic mice. Science338, 949–953. doi: 10.1126/science.1227157
104. Luk, K. C., Kehm, V. M., Zhang, B., O’Brien, P., Trojanowski, J. Q., and Lee, V. M. Y. (2012b). Intracerebral inoculation of pathological α-synuclein initiates a rapidly progressive neurodegenerative α-synucleinopathy in mice. J. Exp. Med. 209, 975–986. doi: 10.1084/jem.20112457
105. Luk, K. C., and Lee, V. M.-Y. (2014). Modeling Lewy pathology propagation in Parkinson’s disease. Parkinsonism Relat. Disord. 20(Suppl. 1), S85–S87. doi: 10.1016/S1353-8020(13)70022–70021
106. Maekawa, T., Mori, S., Sasaki, Y., Miyajima, T., Azuma, S., Ohta, E., et al. (2012). The I2020T Leucine-rich repeat kinase 2 transgenic mouse exhibits impaired locomotive ability accompanied by dopaminergic neuron abnormalities. Mol. Neurodegener.7, 15. doi: 10.1186/1750-1326-715
107. Manning-Bog, A. B., McCormack, A. L., Li, J., Uversky, V. N., Fink, A. L., and Di Monte, D. A. (2002). The herbicide paraquat causes up-regulation and aggregation of alpha-synuclein in mice: paraquat and alpha-synuclein. J. Biol. Chem.277, 1641–1644. doi: 10.1074/jbc.C100560200
108. Martella, G., Platania, P., Vita, D., Sciamanna, G., Cuomo, D., Tassone, A., et al. (2009). Enhanced sensitivity to group II mGlu receptor activation at corticostriatal synapses in mice lacking the familial parkinsonism-linked genes PINK1 or Parkin. Exp. Neurol. 215, 388–396. doi: 10.1016/j.expneurol.2008.11.001
109. Masliah, E., Rockenstein, E., Veinbergs, I., Mallory, M., Hashimoto, M., Takeda, A., et al. (2000). Dopaminergic loss and inclusion body formation in alpha-synuclein mice: implications for neurodegenerative disorders. Science287, 1265–1269. doi: 10.1126/science.287.5456.1265
110. Masuda-Suzukake, M., Nonaka, T., Hosokawa, M., Kubo, M., Shimozawa, A., Akiyama, H., et al. (2014). Pathological alpha-synuclein propagates through neural networks. Acta Neuropathol. Commun.2, 88. doi: 10.1186/PREACCEPT-1296467154135944
111. Matsui, H., Uemura, N., Yamakado, H., Takeda, S., and Takahashi, R. (2014). Exploring the pathogenetic mechanisms underlying Parkinson’s disease in medaka fish. J. Parkinsons. Dis.4, 301–310. doi: 10.3233/JPD-130289
112. Matsuoka, Y., Vila, M., Lincoln, S., McCormack, A., Picciano, M., LaFrancois, J., et al. (2001). Lack of nigral pathology in transgenic mice expressing human alpha-synuclein driven by the tyrosine hydroxylase promoter. Neurobiol. Dis.8, 535–539. doi: 10.1006/nbdi.2001.0392
113. McCormack, A. L., Thiruchelvam, M., Manning-Bog, A. B., Thiffault, C., Langston, J. W., Cory-Slechta, D. A., et al. (2002). Environmental risk factors and Parkinson’s disease: selective degeneration of nigral dopaminergic neurons caused by the herbicide paraquat. Neurobiol. Dis. 10, 119–127. doi: 10.1006/nbdi.2002.0507
114. McDowell, K., and Chesselet, M.-F. (2012). Animal models of the non-motor features of Parkinson’s disease. Neurobiol. Dis.46, 597–606. doi: 10.1016/j.nbd.2011.12.040
115. Melrose, H. L., Dächsel, J. C., Behrouz, B., Lincoln, S. J., Yue, M., Hinkle, K. M., et al. (2010). Impaired dopaminergic neurotransmission and microtubule-associated protein tau alterations in human LRRK2 transgenic mice. Neurobiol. Dis.40, 503–517. doi: 10.1016/j.nbd.2010.07.010
116. Meredith, G. E., Totterdell, S., Potashkin, J. A., and Surmeier, D. J. (2008). Modeling PD pathogenesis in mice: advantages of a chronic MPTP protocol. Park. Relat Disord14(Suppl. 2), S112–S115. doi: 10.1016/j.parkreldis.2008.04.012
117. Miller, G. W. (2007). Paraquat: the red herring of Parkinson’s disease research. Toxicol. Sci.100, 1–2. doi: 10.1093/toxsci/kfm223
118. Miller, R. M., Kiser, G. L., Kaysser-Kranich, T., Casaceli, C., Colla, E., Lee, M. K., et al. (2007). Wild-type and mutant alpha-synuclein induce a multi-component gene expression profile consistent with shared pathophysiology in different transgenic mouse models of PD. Exp. Neurol.204, 421–432. doi: 10.1016/j.expneurol.2006.12.005
119. Morais, V. A., Haddad, D., Craessaerts, K., De Bock, P.-J., Swerts, J., Vilain, S., et al. (2014). PINK1 loss-of-function mutations affect mitochondrial complex I activity via NdufA10 ubiquinone uncoupling. Science344, 203–207. doi: 10.1126/science.1249161
120. Moratalla, R., Quinn, B., DeLanney, L. E., Irwin, I., Langston, J. W., and Gray-biel, A. M. (1992). Differential vulnerability of primate caudate-putamen and striosome-matrix dopamine systems to the neurotoxic effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Proc. Natl. Acad. Sci. U.S.A.89, 3859–3863. doi: 10.1073/pnas.89.9.3859
121. Morin, N., Jourdain, V. A., and Di Paolo, T. (2014). Modeling dyskinesia in animal models of Parkinson disease. Exp. Neurol.256, 105–116. doi: 10.1016/j.expneurol.2013.01.024
122. Morrow, B. A., Roth, R. H., Redmond, D. E., and Elsworth, J. D. (2011). Impact of methamphetamine on dopamine neurons in primates is dependent on age: implications for development of Parkinson’s disease. Neuroscience189, 277–285. doi: 10.1016/j.neuroscience.2011.05.046
123. Muthane, U., Ramsay, K. A., Jiang, H., Jackson-Lewis, V., Donaldson, D., Fernando, S., et al. (1994). Differences in nigral neuron number and sensitivity to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in C57/bl and CD-1 mice. Exp. Neurol.126, 195–204. doi: 10.1006/exnr.1994.1058
124. Ness, D., Ren, Z., Gardai, S., Sharpnack, D., Johnson, V. J., Brennan, R. J., et al. (2013). Leucine-rich repeat kinase 2 (LRRK2)-deficient rats exhibit renal tubule injury and perturbations in metabolic and immunological homeostasis. PLoS ONE8:e66164. doi: 10.1371/journal.pone.0066164
125. Nieto, M., Gil-Bea, F. J., Dalfó, E., Cuadrado, M., Cabodevilla, F., Sánchez, B., et al. (2006). Increased sensitivity to MPTP in human alpha-synuclein A30P trans-genic mice. Neurobiol. Aging 27, 848–856. doi: 10.1016/j.neurobiolaging.2005.04.010
126. Nordström, U., Beauvais, G., Ghosh, A., Sasidharan, B. C. P., Lundblad, M., Fuchs, J., et al. (2014). Progressive nigrostriatal terminal dysfunction and degeneration in the engrailed1 heterozygous mouse model of Parkinson’s disease. Neurobiol. Dis. doi: 10.1016/j.nbd.2014.09.012
127. Oaks, A. W., Frankfurt, M., Finkelstein, D. I., and Sidhu, A. (2013). Age-dependent effects of A53T alpha-synuclein on behavior and dopaminergic function. PLoS ONE8:e60378. doi: 10.1371/journal.pone.0060378
128. Obeso, J. A., Rodriguez-Oroz, M. C., Stamelou, M., Bhatia, K. P., and Burn, D. J. (2014). The expanding universe of disorders of the basal ganglia. Lancet 384, 523–531. doi: 10.1016/S0140-6736(13)62418–62416
129. O’Callaghan, J. P., and Miller, D. B. (1994). Neurotoxicity profiles of substituted amphetamines in the C57BL/6J mouse. J. Pharmacol. Exp. Ther. 270, 741–751.
130. Oliveras-Salvá, M., Macchi, F., Coessens, V., Deleersnijder, A., Gérard, M., Van der Perren, A., et al. (2014). Alpha-synuclein-induced neurodegeneration is exacerbated in PINK1 knockout mice. Neurobiol. Aging35, 2625–2636. doi: 10.1016/j.neurobiolaging.2014.04.032
131. Oliveras-Salvá, M., Van der Perren, A., Casadei, N., Stroobants, S., Nuber, S., D’Hooge, R., et al. (2013). rAAV2/7 vector-mediated overexpression of alpha-synuclein in mouse substantia nigra induces protein aggregation and progressive dose-dependent neurodegeneration. Mol. Neurodegener. 8, 44. doi: 10.1186/1750-1326-8-44
132. Ono, K., Ikemoto, M., Kawarabayashi, T., Ikeda, M., Nishinakagawa, T., Hosokawa, M., et al. (2009). A chemical chaperone, sodium 4-phenylbutyric acid, attenuates the pathogenic potency in human alpha-synuclein A30P + A53T transgenic mice. Parkinsonism Relat. Disord.15, 649–654. doi: 10.1016/j.parkreldis.2009.03.002
133. Ottolini, D., Calì, T., Negro, A., and Brini, M. (2013). The Parkinson disease-related protein DJ-1 counteracts mitochondrial impairment induced by the tumour suppressor protein p53 by enhancing endoplasmic reticulum-mitochondria tethering. Hum. Mol. Genet.22, 2152–2168. doi: 10.1093/hmg/ddt068
134. Palacino, J. J., Sagi, D., Goldberg, M. S., Krauss, S., Motz, C., Wacker, M., et al. (2004). Mitochondrial dysfunction and oxidative damage in parkin-deficient mice. J. Biol. Chem.279, 18614–18622. doi: 10.1074/jbc.M401135200
135. Pan-Montojo, F., Anichtchik, O., Dening, Y., Knels, L., Pursche, S., Jung, R., et al. (2010). Progression of Parkinson’s disease pathology is reproduced by intragastric administration of rotenone in mice. PLoS ONE5:e8762. doi: 10.1371/journal.pone.0008762
136. Paumier, K. L., Sukoff Rizzo, S. J., Berger, Z., Chen, Y., Gonzales, C., Kaftan, E., et al. (2013). Behavioral characterization of A53T mice reveals early and late stage deficits related to Parkinson’s disease. PLoS ONE8:e70274. doi: 10.1371/journal.pone.0070274
137. Perez, F. A., and Palmiter, R. D. (2005). Parkin-deficient mice are not a robust model of parkinsonism. Proc. Natl. Acad. Sci. U.S.A.102, 2174–2179. doi: 10.1073/pnas.0409598102
138. Periquet, M., Latouche, M., Lohmann, E., Rawal, N., De Michele, G., Ricard, S., et al. (2003). Parkin mutations are frequent in patients with isolated early-onset parkinsonism. Brain126, 1271–1278. doi: 10.1093/brain/awg136
139. Pham, T. T., Giesert, F., Röthig, A., Floss, T., Kallnik, M., Weindl, K., et al. (2010). DJ-1-deficient mice show less TH-positive neurons in the ventral tegmental area and exhibit non-motoric behavioural impairments. Genes Brain Behav. 9, 305–317. doi: 10.1111/j.1601-183X.2009.00559.x
140. Pifl, C., Rajput, A., Reither, H., Blesa, J., Cavada, C., Obeso, J. A, et al. (2014). Is Parkinson’s disease a vesicular dopamine storage disorder? Evidence from a study in isolated synaptic vesicles of human and nonhuman primate striatum. J. Neurosci. 34, 8210–8218. doi: 10.1523/JNEUROSCI.5456-13.2014
141. Porras, G., Li, Q., and Bezard, E. (2012). Modeling Parkinson’s disease in primates: the MPTP model. Cold Spring Harb. Perspect. Med. 2, a009308. doi: 10.1101/cshperspect.a009308
142. Pringsheim, T., Jette, N., Frolkis, A., and Steeves, T. D. L. (2014). The prevalence of Parkinson’s disease: a systematic review and meta-analysis. Mov. Disord.29, 1583–1590. doi: 10.1002/mds.25945
143. Przedborski, S., Levivier, M., Jiang, H., Ferreira, M., Jackson-Lewis, V., Donaldson, D., et al. (1995). Dose-dependent lesions of the dopaminergic nigrostriatal pathway induced by intrastriatal injection of 6-hydroxydopamine. Neuroscience67, 631–647. doi: 10.1016/0306-4522(95)00066-R
144. Purisai, M. G., McCormack, A. L., Langston, W. J., Johnston, L. C., and Di Monte, D. A. (2005). Alpha-synuclein expression in the substantia nigra of MPTP-lesioned non-human primates. Neurobiol. Dis.20, 898–906. doi: 10.1016/j.nbd.2005.05.028
145. Puschmann, A. (2013). Monogenic Parkinson’s disease and parkinsonism: clinical phenotypes and frequencies of known mutations. Parkinsonism Relat. Disord.19, 407–415. doi: 10.1016/j.parkreldis.2013.01.020
146. Ramonet, D., Daher, J. P. L., Lin, B. M., Stafa, K., Kim, J., Banerjee, R., et al. (2011). Dopaminergic neuronal loss, reduced neurite complexity and autophagic abnormalities in transgenic mice expressing G2019S mutant LRRK2. PLoS ONE6:e18568. doi: 10.1371/journal.pone.0018568
147. Rappold, P. M., Cui, M., Chesser, A. S., Tibbett, J., Grima, J. C., Duan, L., et al. (2011). Paraquat neurotoxicity is mediated by the dopamine transporter and organic cation transporter-3. Proc. Natl. Acad. Sci. U.S.A.108, 20766–20771. doi: 10.1073/pnas.1115141108
148. Rathke-Hartlieb, S., Kahle, P. J., Neumann, M., Ozmen, L., Haid, S., Okochi, M., et al. (2001). Sensitivity to MPTP is not increased in Parkinson’s disease-associated mutant alpha-synuclein transgenic mice. J. Neurochem.77, 1181–1184. doi: 10.1046/j.1471-4159.2001.00366.x
149. Recasens, A., Dehay, B., Bové, J., Carballo-Carbajal, I., Dovero, S., Pérez-Villalba, A., et al. (2014). Lewy body extracts from Parkinson disease brains trigger α-synuclein pathology and neurodegeneration in mice and monkeys. Ann. Neurol.75, 351–362. doi: 10.1002/ana.24066
150. Rockenstein, E., Mallory, M., Hashimoto, M., Song, D., Shults, C. W., Lang, I., et al. (2002). Differential neuropathological alterations in transgenic mice expressing alpha-synuclein from the platelet-derived growth factor and Thy-1 promoters. J. Neurosci. Res.68, 568–578. doi: 10.1002/jnr.10231
151. Rodríguez Díaz, M., Abdala, P., Barroso-Chinea, P., Obeso, J., and Gonzalez-Hernandez, T. (2001). Motor behavioural changes after intracerebroventricular injection of 6-hydroxydopamine in the rat: an animal model of Parkinson’s disease. Behav. Brain Res.122, 79–92. doi: 10.1016/S0166-4328(01)00168-1
152. Rodriguez-Oroz, M. C., Jahanshahi, M., Krack, P., Litvan, I., Macias, R., Bezard, E., et al. (2009). Initial clinical manifestations of Parkinson’s disease: features and pathophysiological mechanisms. Lancet Neurol. 8, 1128–1139. doi: 10.1016/S1474-4422(09)70293–70295
153. Rousseaux, M. W. C., Marcogliese, P. C., Qu, D., Hewitt, S. J., Seang, S., Kim, R. H., et al. (2012). Progressive dopaminergic cell loss with unilateral-to-bilateral progression in a genetic model of Parkinson disease. Proc. Natl. Acad. Sci. U.S.A.109, 15918–15923. doi: 10.1073/pnas.1205102109
154. Rudenko, I. N., and Cookson, M. R. (2014). Heterogeneity of leucine-rich repeat kinase 2 mutations: genetics, mechanisms and therapeutic implications. Neurotherapeutics4, 738–750. doi: 10.1007/s13311-014-0284-z
155. Sacino, A. N., Brooks, M., Thomas, M. A., McKinney, A. B., Lee, S., Regenhardt, R. W., et al. (2014). Intramuscular injection of α-synuclein induces CNS α-synuclein pathology and a rapid-onset motor phenotype in transgenic mice. Proc. Natl. Acad. Sci. U.S.A.111, 10732–10737. doi: 10.1073/pnas.1321785111
156. Sanchez, G., Varaschin, R. K., Büeler, H., Marcogliese, P. C., Park, D. S., and Trudeau, L.-E. (2014). Unaltered striatal dopamine release levels in young Parkin knockout, Pink1 knockout, DJ-1 knockout and LRRK2 R1441G transgenic mice. PLoS ONE9:e94826. doi: 10.1371/journal.pone.0094826
157. Sauer, H., and Oertel, W. H. (1994). Progressive degeneration of nigros-triatal dopamine neurons following intrastriatal terminal lesions with 6-hydroxydopamine: a combined retrograde tracing and immunocytochemical study in the rat. Neuroscience59, 401–415. doi: 10.1016/0306-4522(94)90605-X
158. Scarffe, L. A., Stevens, D. A., Dawson, V. L., and Dawson, T. M. (2014). Parkin and PINK1: much more than mitophagy. Trends Neurosci. 37, 315–324. doi: 10.1016/j.tins.2014.03.004
159. Schallert, T., Fleming, S. M., Leasure, J. L., Tillerson, J. L., and Bland, S. T. (2000). CNS plasticity and assessment of forelimb sensorimotor outcome in unilateral rat models of stroke, cortical ablation, parkinsonism and spinal cord injury. Neuropharmacology39, 777–787. doi: 10.1016/S0028-3908(00)00005-8
160. Schapira, A. H. V., Olanow, C. W., Greenamyre, J. T., and Bezard, E. (2014). Slowing of neurodegeneration in Parkinson’s disease and Huntington’s disease: future therapeutic perspectives. Lancet 384, 545–555. doi: 10.1016/S0140-6736(14)61010–61012
161. Schultheis, P. J., Fleming, S. M., Clippinger, A. K., Lewis, J., Tsunemi, T., Giasson, B., et al. (2013). Atp13a2-deficient mice exhibit neuronal ceroid lipofuscinosis, limited α-synuclein accumulation and age-dependent sensorimotor deficits. Hum. Mol. Genet.22, 2067–2082. doi: 10.1093/hmg/ddt057
162. Seniuk, N. A., Tatton, W. G., and Greenwood, C. E. (1990). Dose-dependent destruction of the coeruleus-cortical and nigral-striatal projections by MPTP. Brain Res. 527, 7–20. doi: 10.1016/0006-8993(90)91055-L
163. Sherer, T. B., Kim, J. H., Betarbet, R., and Greenamyre, J. T. (2003). Subcutaneous rotenone exposure causes highly selective dopaminergic degeneration and alpha-synuclein aggregation. Exp. Neurol.179, 9–16. doi: 10.1006/exnr.2002.8072
164. Shimoji, M., Zhang, L., Mandir, A. S., Dawson, V. L., and Dawson, T. M. (2005). Absence of inclusion body formation in the MPTP mouse model of Parkinson’s disease. Brain Res. Mol. Brain Res.134, 103–108. doi: 10.1016/j.molbrainres.2005.01.012
165. Singleton, A. B., Farrer, M., Johnson, J., Singleton, A., Hague, S., Kachergus, J., et al. (2003). alpha-Synuclein locus triplication causes Parkinson’s disease. Science 302, 841. doi: 10.1126/science.1090278
166. Snow, B. J., Vingerhoets, F. J., Langston, J. W., Tetrud, J. W., Sossi, V., and Calne, D. B. (2000). Pattern of dopaminergic loss in the striatum of humans with MPTP induced parkinsonism. J. Neurol. Neurosurg. Psychiatry68, 313–316. doi: 10.1136/jnnp.68.3.313
167. Sonsalla, P. K., Jochnowitz, N. D., Zeevalk, G. D., Oostveen, J. A., and Hall, E. D. (1996). Treatment of mice with methamphetamine produces cell loss in the substantia nigra. Brain Res. 738, 172–175. doi: 10.1016/0006-8993(96)00995-X
168. Sotiriou, E., Vassilatis, D. K., Vila, M., and Stefanis, L. (2010). Selective noradrenergic vulnerability in α-synuclein transgenic mice. Neurobiol. Aging 31, 2103–2114. doi: 10.1016/j.neurobiolaging.2008.11.010
169. Su, X., Federoff, H. J., and Maguire-Zeiss, K. A. (2009). Mutant alpha-synuclein overexpression mediates early proinflammatory activity. Neurotox. Res.16, 238–254. doi: 10.1007/s12640-009-9053-x
170. Sziráki, I., Kardos, V., Patthy, M., Pátfalusi, M., and Budai, G. (1994). Methamphetamine protects against MPTP neurotoxicity in C57BL mice. Eur. J. Pharmacol. 251, 311–314. doi: 10.1016/0014-2999(94)90416-2
171. Takahashi, N., Miner, L. L., Sora, I., Ujike, H., Revay, R. S., Kostic, V., et al. (1997). VMAT2 knockout mice: heterozygotes display reduced amphetamine-conditioned reward, enhanced amphetamine locomotion, and enhanced MPTP toxicity. Proc. Natl. Acad. Sci. U.S.A. 94, 9938–9943.
172. Takahashi, R. N., Rogerio, R., and Zanin, M. (1989). Maneb enhances MPTP neurotoxicity in mice. Res. Commun. Chem. Pathol. Pharmacol.66, 167–170.
173. Taylor, T. N., Alter, S. P., Wang, M., Goldstein, D. S., and Miller, G. W. (2014). Reduced vesicular storage of catecholamines causes progressive degeneration in the locus ceruleus. Neuropharmacology76(Pt A), 97–105. doi: 10.1016/j.neuropharm.2013.08.033
174. Taylor, T. N., Caudle, W. M., and Miller, G. W. (2011). VMAT2-deficient mice display nigral and extranigral pathology and motor and nonmotor symptoms of Parkinson’s disease. Parkinsons Dis. 2011, 124165. doi: 10.4061/2011/124165
175. Taylor, T. N., Greene, J. G., and Miller, G. W. (2010). Behavioral phenotyp-ing of mouse models of Parkinson’s disease. Behav. Brain Res.211, 1–10. doi: 10.1016/j.bbr.2010.03.004
176. Thiruchelvam, M., Brockel, B. J., Richfield, E. K., Baggs, R. B., and Cory-Slechta, D. A. (2000). Potentiated and preferential effects of combined paraquat and maneb on nigrostriatal dopamine systems: environmental risk factors for Parkinson’s disease? Brain Res. 873, 225–234. doi: 10.1016/S0006-8993(00) 02496-3
177. Thiruchelvam, M., McCormack, A., Richfield, E. K., Baggs, R. B., Tank, A. W., Di Monte, D. A., et al. (2003). Age-related irreversible progressive nigrostriatal dopaminergic neurotoxicity in the paraquat and maneb model of the Parkinson’s disease phenotype. Eur. J. Neurosci. 18, 589–600. doi: 10.1046/j.1460-9568.2003.02781.x
178. Thiruchelvam, M. J., Powers, J. M., Cory-Slechta, D. A., and Richfield, E. K. (2004). Risk factors for dopaminergic neuron loss in human alpha-synuclein transgenic mice. Eur. J. Neurosci. 19, 845–854. doi: 10.1111/j.0953-816X.2004.03139.x
179. Thrash, B., Thiruchelvan, K., Ahuja, M., Suppiramaniam, V., and Dhanasekaran, M. (2009). Methamphetamine-induced neurotoxicity: the road to Parkinson’s disease. Pharmacol. Rep. 61, 966–977. doi: 10.1016/S1734-1140(09)70158-6
180. Tieu, K. (2011). A guide to neurotoxic animal models of Parkinson’s disease. Cold Spring Harb. Perspect. Med. 1, a009316. doi: 10.1101/cshperspect.a009316
181. Tong, Y., Pisani, A., Martella, G., Karouani, M., Yamaguchi, H., Pothos, E. N., et al. (2009). R1441C mutation in LRRK2 impairs dopaminergic neuro-transmission in mice. Proc. Natl. Acad. Sci. U.S.A.106, 14622–14627. doi: 10.1073/pnas.0906334106
182. Tong, Y., Yamaguchi, H., Giaime, E., Boyle, S., Kopan, R., Kelleher, R. J., et al. (2010). Loss of leucine-rich repeat kinase 2 causes impairment of protein degradation pathways, accumulation of alpha-synuclein, and apoptotic cell death inaged mice. Proc. Natl. Acad. Sci. U.S.A. 107, 9879–9884. doi: 10.1073/pnas.1004676107
183. Trulson, M. E., Cannon, M. S., Faegg, T. S., and Raese, J. D. (1985). Effects of chronic methamphetamine on the nigral-striatal dopamine system in rat brain: tyrosine hydroxylase immunochemistry and quantitative light microscopic studies. Brain Res. Bull. 15, 569–577. doi: 10.1016/0361-9230(85)90206–90200
184. Tsika, E., Kannan, M., Foo, C. S.-Y., Dikeman, D., Glauser, L., Gellhaar, S., et al. (2014). Conditional expression of Parkinson’s disease-related R1441C LRRK2 in midbrain dopaminergic neurons of mice causes nuclear abnormalities without neurodegeneration. Neurobiol. Dis. 71, 345–358. doi: 10.1016/j.nbd.2014.08.027
185. Ulusoy, A., Sahin, G., and Kirik, D. (2010). Presynaptic dopaminergic compartment determines the susceptibility to L-DOPA-induced dyskinesia in rats. Proc. Natl. Acad. Sci. U.S.A.107, 13159–13164. doi: 10.1073/pnas.1003432107
186. Ungerstedt, U. (1968). 6-Hydroxy-dopamine induced degeneration of central monoamine neurons. Eur. J. Pharmacol. 5, 107–110. doi: 10.1016/0014-2999(68)90164-7
187. van den Munckhof, P., Luk, K. C., Ste-Marie, L., Montgomery, J., Blanchet, P. J., Sadikot, A. F., et al. (2003). Pitx3 is required for motor activity and for survival of a subset of midbrain dopaminergic neurons. Development130, 2535–2542. doi: 10.1242/dev.00464
188. van der Putten, H., Wiederhold, K. H., Probst, A., Barbieri, S., Mistl, C., Danner, S., et al. (2000). Neuropathology in mice expressing human alpha-synuclein. J. Neurosci.20, 6021–6029.
189. Van Rompuy, A.-S., Lobbestael, E., Van der Perren, A., Van den Haute, C., and Baekelandt, V. (2014). Long-term overexpression of human wild-type and T240R mutant Parkin in rat substantia nigra induces progressive dopamin-ergic neurodegeneration. J. Neuropathol. Exp. Neurol.73, 159–174. doi: 10.1097/NEN.0000000000000039
190. Vekrellis, K., Xilouri, M., Emmanouilidou, E., Rideout, H. J., and Stefanis, L. (2011). Pathological roles of α-synuclein in neurological disorders. Lancet Neurol. 10, 1015–1025. doi: 10.1016/S1474-4422(11)70213–70217
191. Vila, M., Vukosavic, S., Jackson-Lewis, V., Neystat, M., Jakowec, M., and Przedborski, S. (2000). Alpha-synuclein up-regulation in substantia nigra dopaminergic neurons following administration of the parkinsonian toxin MPTP. J. Neurochem. 74, 721–729. doi: 10.1046/j.1471-4159.2000.740721.x
192. Vincow, E. S., Merrihew, G., Thomas, R. E., Shulman, N. J., Beyer, R. P., MacCoss, M. J., et al. (2013). The PINK1-Parkin pathway promotes both mitophagy and selective respiratory chain turnover in vivo. Proc. Natl. Acad. Sci. U.S.A.110, 6400–6405. doi: 10.1073/pnas.1221132110
193. Von Coelln, R., Thomas, B., Savitt, J. M., Lim, K. L., Sasaki, M., Hess, E. J., et al. (2004). Loss of locus coeruleus neurons and reduced startle in parkin null mice. Proc. Natl. Acad. Sci. U.S.A. 101, 10744–10749. doi: 10.1073/pnas.0401297101
194. Wagner, G. C., Seiden, L. S., and Schuster, C. R. (1979). Methamphetamine-induced changes in brain catecholamines in rats and guinea pigs. Drug Alcohol Depend. 4, 435–438. doi: 10.1016/0376-8716(79)90076–90070
195. Wakamatsu, M., Ishii, A., Iwata, S., Sakagami, J., Ukai, Y., Ono, M., et al. (2008). Selective loss of nigral dopamine neurons induced by overexpression of truncated human alpha-synuclein in mice. Neurobiol. Aging29, 574–585. doi: 10.1016/j.neurobiolaging.2006.11.017
196. Winner, B., Melrose, H. L., Zhao, C., Hinkle, K. M., Yue, M., Kent, C., et al. (2011). Adult neurogenesis and neurite outgrowth are impaired in LRRK2 G2019S mice. Neurobiol. Dis.41, 706–716. doi: 10.1016/j.nbd.2010.12.008
197. Xiong, N., Huang, J., Zhang, Z., Zhang, Z., Xiong, J., Liu, X., et al. (2009). Stereo-taxical infusion of rotenone: a reliable rodent model for Parkinson’s disease. PLoS ONE4:e7878. doi: 10.1371/journal.pone.0007878
198. Yang, X., and Xu, Y. (2014). Mutations in the ATP13A2 gene and parkinsonism: a preliminary review. Biomed Res. Int.2014, 371256. doi: 10.1155/2014/371256
199. Zhang, H., Duan, C., and Yang, H. (2014). Defective autophagy in Parkinson’s disease: lessons from genetics. Mol. Neurobiol. doi: 10.1007/s12035-014-8787–8785 [Epub ahead of print].
200. Zhang, L., Le, W., Xie, W., and Dani, J. A. (2012). Age-related changes in dopamine signaling in Nurr1 deficient mice as a model of Parkinson’s disease. Neurobiol. Aging 33, 1001.e7–1001.e16. doi: 10.1016/j.neurobiolaging.2011.03.022
201. Zhou, H., Huang, C., Tong, J., Hong, W. C., Liu, Y.-J., and Xia, X.-G. (2011). Temporal expression of mutant LRRK2 in adult rats impairs dopamine reuptake. Int. J. Biol. Sci. 7, 753–761. doi: 10.7150/ijbs.7.753
202. Zhu, X.-R., Maskri, L., Herold, C., Bader, V., Stichel, C. C., Güntürkün, O., et al. (2007). Non-motor behavioural impairments in parkin-deficient mice. Eur. J. Neurosci.26, 1902–1911. doi: 10.1111/j.1460-9568.2007.05812.x