Therapeutic strategies in Parkinson's disease: What we have learned from animal models

Annals of the New York Academy of Sciences

Volumn 1338, Issue 1, 2015, Pages 16-37

  Valadas, Jorge S ^a,b   Vos, Melissa ^a,b   Verstreken, Patrik ^a,b  

^a VIB Center for the Biology of Disease   (United States)

^b UNIVERSITY OF LEUVEN   (Belgium)

Author keywords

Animal models; Mitochondria; Parkinson's disease; Synaptic transmission; Therapeutic strategies

Indexed keywords

1,2,3,6 TETRAHYDRO 1 METHYL 4 PHENYLPYRIDINE; ALPHA SYNUCLEIN; DJ 1 PROTEIN; DOPAMINE RECEPTOR STIMULATING AGENT; GLUCOSYLCERAMIDASE; LEUCINE RICH REPEAT KINASE 2; LEVODOPA; MONOAMINE OXIDASE INHIBITOR; PARKIN; SERINE PROTEINASE OMI; SYNAPTOJANIN; UBIQUITIN THIOLESTERASE;

ARTICLE; BRAIN MITOCHONDRION; DISEASE MODEL; DRUG TARGETING; GENE MUTATION; NERVE DEGENERATION; NONHUMAN; PARKINSON DISEASE; SYNAPTIC TRANSMISSION; ANIMAL; GENETICS; MITOCHONDRION; PATHOPHYSIOLOGY; PERSONALIZED MEDICINE; PHYSIOLOGY;

ANIMALIA;

ANIMALS; DISEASE MODELS, ANIMAL; INDIVIDUALIZED MEDICINE; MITOCHONDRIA; PARKINSON DISEASE; SYNAPTIC TRANSMISSION;

EID: 84925012167     PISSN: 00778923     EISSN: 17496632     Source Type: Journal    
DOI: 10.1111/nyas.12577     Document Type: Article

References (210)

1. Dorsey, E.R., R. Constantinescu, J.P., Thompson, et al. 2007. Projected number of people with Parkinson disease in the most populous nations, 2005 through 2030. Neurology 68: 384-386.
2. Fahn, S & J. Jankovic . 2007. Principles and Practice of Movement Disorders. Churchill Livingstone Elsevier.
3. Wood, L.D., J.J. Neumiller, S.M. Setter, et al. 2010. Clinical review of treatment options for select nonmotor symptoms of Parkinson's disease. Am. J. Geriatr. Pharmacother. 8: 294-315.
4. Fan, H., S. Chen, H. Harn, et al. 2013. Parkinson's disease: from genetics to treatments. Cell Transplant. 22: 639-652.
5. Davie, C.A. 2008. A review of Parkinson's disease. Br. Med. Bull. 86: 109-127.
6. De Lau, L.M. & M.M. Breteler . 2006. Epidemiology of Parkinson's disease. Lancet Neurol. 5: 525-535.
7. Tanner, C.M., F. Kamel, G.W., Ross, et al. 2011. Rotenone, paraquat, and Parkinson's disease. Environ. Health Perspect. 119: 866-872.
8. Corti, O., S. Lesage & A. Brice . 2011. What genetics tells us about the causes and mechanisms of Parkinson's disease. Physiol. Rev. 91: 1161-1218.
9. Liu, G., L. Aliaga & H. Cai . 2012. α-Synuclein, LRRK2 and their interplay in Parkinson's disease. Future Neurol 7: 145-153.
10. Davis, G.C., A.C. Williams, S.P. Markey, et al. 1979. Chronic Parkinsonism secondary to intravenous injection of meperidine analogues. Psychiatry Res. 1: 249-254.
11. Lesage, S. & A. Brice . 2009. Parkinson's disease: from monogenic forms to genetic susceptibility factors. Hum. Mol. Genet. 18: R48-R59.
12. Hirsch, E., A.M. Graybiel & Y.A. Agid . 1988. Melanized dopaminergic neurons are differentially susceptible to degeneration in Parkinson's disease. Nature 334: 345-348.
13. Hodge, G. & L. Butcher . 1980. Pars compacta of the Substantia nigra modulates motor activity but is not involved importantly in regulating food and water intake. Naunyn Schmiedebergs Arch Pharmacol 313: 51-67.
14. Cabin, D.E., K. Shimazu, D. Murphy, et al. 2002. Synaptic vesicle depletion correlates with attenuated synaptic responses to prolonged repetitive stimulation in mice lacking α-synuclein. J. Neurosci. 22: 8797-8807.
15. Cheng, F., G. Vivacqua & S. Yu . 2011. The role of α-synuclein in neurotransmission and synaptic plasticity. J. Chem. Neuroanat. 42: 242-248.
16. Clayton, D.F. & J.M. George . 1998. The synucleins: a family of proteins involved in synaptic function, plasticity, neurodegeneration and disease. Trends Neurosci. 21: 249-254.
17. Kuwahara, T., A. Koyama, S. Koyama, et al. 2008. A systematic RNAi screen reveals involvement of endocytic pathway in neuronal dysfunction in α-synuclein transgenic C. elegans. Hum. Mol. Genet. 17: 2997-3009.
18. Nemani, V.M., W. Lu, V. Berge, et al. 2010. Increased expression of α-synuclein reduces neurotransmitter release by inhibiting synaptic vesicle reclustering after endocytosis. Neuron 65: 66-79.
19. Mandemakers, W., V.A. Morais & B. De Strooper . 2007. A cell biological perspective on mitochondrial dysfunction in Parkinson disease and other neurodegenerative diseases. J. Cell Sci. 120: 1707-1716.
20. Matta, S., K. Van Kolen, R., da Cunha, et al. 2012. LRRK2 controls an EndoA phosphorylation cycle in synaptic endocytosis. Neuron 75: 1008-1021.
21. Yun, H.J., J. Park, D.H. Ho, et al. 2013. LRRK2 phosphorylates Snapin and inhibits interaction of Snapin with SNAP-25. Exp. Mol. Med. 45: e36.
22. Piccoli, G., F. Onofri, M.D. Cirnaru, et al. 2014. LRRK2 binds to neuronal vesicles through protein interactions mediated by its C-terminal WD40 domain. Mol. Cell. Biol. 34: 2147-2161.
23. Piccoli, G., S.B. Condliffe, M. Bauer, et al. 2011. LRRK2 controls synaptic vesicle storage and mobilization within the recycling pool. J. Neurosci. 31: 2225-2237.
24. Picconi, B., G. Piccoli & P. Calabresi . 2012. Synaptic Plast. Vol. 970. M. R. Kreutz & C. Sala, Eds.: 553-572. Vienna: Springer.
25. Masliah, E. 2000. Dopaminergic loss and inclusion body formation in synuclein mice: implications for neurodegenerative disorders. Science 287: 1265-1269.
26. Lee, S., Y. Imai, S. Gehrke, et al. 2012. The synaptic function of LRRK2. Biochem. Soc. Trans. 40: 1047-1051.
27. Lin, X., L. Parisiadou, X.-L., Gu, et al. 2009. Leucine-rich repeat kinase 2 regulates the progression of neuropathology induced by Parkinson's-disease-related mutant α-synuclein. Neuron 64: 807-827.
28. Polymeropoulos, M.H., C. Lavedan, E. Leroy, et al. 1997. Mutation in the α-synuclein gene identified in families with Parkinson's disease. Science 276: 2045-2047.
29. Marques, O & T.F. Outeiro . 2012. α-Synuclein: from secretion to dysfunction and death. Cell Death Dis. 3: e350.
30. Shults, C.W. 2006. Lewy bodies. Proc. Natl. Acad. Sci. U. S. A. 103: 1661-1668.
31. Klein, C & A. Westenberger . 2012. Genetics of Parkinson's disease. Cold Spring Harb. Perspect. Med. 2: a008888.
32. Krüger, R., W. Kuhn, T. Müller, et al. 1998. Ala30Pro mutation in the gene encoding α-synuclein in Parkinson's disease. Nat. Genet. 18: 106-108.
33. Zarranz, J.J., J. Alegre, J.C. Gómez-Esteban, et al. 2004. The new mutation, E46K, of α-synuclein causes Parkinson and Lewy body dementia. Ann. Neurol. 55: 164-173.
34. Chartier-Harlin, M.C., J. Kachergus, C. Roumier, et al. 2004. α-Synuclein locus duplication as a cause of familial Parkinson's disease. Lancet 364: 1167-1169.
35. Jo, E., J. McLaurin, C.M., Yip, et al. 2000. α-Synuclein membrane interactions and lipid specificity. J. Biol. Chem. 275: 34328-34334.
36. Fortin, D.L., V.M. Nemani, S.M. Voglmaier, et al. 2005. Neural activity controls the synaptic accumulation of α-synuclein. J. Neurosci. 25: 10913-10921.
37. Kamp, F. & K. Beyer . 2006. Binding of α-synuclein affects the lipid packing in bilayers of small vesicles. J. Biol. Chem. 281: 9251-9259.
38. Diao, J., J. Burré, S. Vivona, et al. 2013. Native α-synuclein induces clustering of synaptic-vesicle mimics via binding to phospholipids and synaptobrevin-2/VAMP2. Elife 2: e00592.
39. Burré, J., M. Sharma, T. Tsetsenis, et al. 2010. α-synuclein promotes SNARE-complex assembly in vivo and in vitro. Science 329: 1663-1667.
40. Burré, J., M. Sharma & T.C. Südhof . 2012. Systematic mutagenesis of α-synuclein reveals distinct sequence requirements for physiological and pathological activities. J. Neurosci. 32: 15227-152242.
41. Garcia-Reitböck, P., O. Anichtchik, A. Bellucci, et al. 2010. SNARE protein redistribution and synaptic failure in a transgenic mouse model of Parkinson's disease. Brain 133: 2032-2044.
42. Volles, M.J. & P.T. Lansbury . 2002. Vesicle permeabilization by protofibrillar α-synuclein is sensitive to Parkinson's disease-linked mutations and occurs by a pore-like mechanism. Biochemistry 41: 4595-4602.
43. Murphy, D.D., S.M. Rueter, J.Q. Trojanowski, et al. 2000. Synucleins are developmentally expressed, and α-synuclein regulates the size of the presynaptic vesicular pool in primary hippocampal neurons. J. Neurosci. 20: 3214-3220.
44. Outeiro, T.F. & S. Lindquist . 2003. Yeast cells provide insight into α-synuclein biology and pathobiology. Science 302: 1772-1775.
45. Overk, C.R. & E. Masliah . 2014. Pathogenesis of synaptic degeneration in Alzheimer's disease and Lewy body disease. Biochem. Pharmacol. 88: 508-516.
46. Chesselet, M.-F., F. Richter, C. Zhu, et al. 2012. A progressive mouse model of Parkinson's disease: the Thy1-aSyn ("Line 61") mice. Neurotherapeutics 9: 297-314.
47. Martin, L.J., Y. Pan, A.C. Price, et al. 2006. Parkinson's disease α-synuclein transgenic mice develop neuronal mitochondrial degeneration and cell death. J. Neurosci. 26: 41-50.
48. Rockenstein, E., M. Mallory, M. Hashimoto, et al. 2002. Differential neuropathological alterations in transgenic mice expressing α-synuclein from the platelet-derived growth factor and Thy-1 promoters. J. Neurosci. Res. 68: 568-578.
49. Buchman, V.L. & N. Ninkina . 2008. Modulation of α-synuclein expression in transgenic animals for modelling synucleinopathies-is the juice worth the squeeze? Neurotox. Res. 14: 329-341.
50. Auluck, P.K., H.Y.E. Chan, J.Q. Trojanowski, et al. 2002. Chaperone suppression of α-synuclein toxicity in a Drosophila model for Parkinson's disease. Science 295: 865-868.
51. Feany, M.B. & W.W. Bender . 2000. A Drosophila model of Parkinson's disease. Nature 404: 394-398.
52. Kontopoulos, E., J.D. Parvin & MB. Feany . 2006. α-Synuclein acts in the nucleus to inhibit histone acetylation and promote neurotoxicity. Hum. Mol. Genet. 15: 3012-3023.
53. Lelan, F., C. Boyer, R. Thinard, et al. 2011. Effects of human α-synuclein A53T-A30P mutations on SVZ and local olfactory bulb cell proliferation in a transgenic rat model of Parkinson disease. Parkinsons. Dis. 2011: 987084.
54. Matsuoka, Y., M. Vila, S. Lincoln, et al. 2001. Lack of nigral pathology in transgenic mice expressing human α-synuclein driven by the tyrosine hydroxylase promoter. Neurobiol. Dis. 8: 535-539.
55. Murray, IV.J., B.I. Giasson, S.M. Quinn, et al. 2003. Role of α-synuclein carboxy-terminus on fibril formation in vitro. Biochemistry 42: 8530-8540.
56. Bezard, E., Z. Yue, D. Kirik, et al. 2013. Animal models of Parkinson's disease: limits and relevance to neuroprotection studies. Mov. Disord. 28: 61-70.
57. Michell, A.W., G.K. Tofaris, H. Gossage, et al. 2007. The effect of truncated human α-synuclein (1-120) on dopaminergic cells in a transgenic mouse model of Parkinson's disease. Cell Transplant. 16: 461-474.
58. Lee, H., S Patel & S. Lee . 2005. Intravesicular localization and exocytosis of α-synuclein and its aggregates. J. Neurosci. 25: 6016-6024.
59. Diógenes, M.J., R.B. Dias, D.M. Rombo, et al. 2012. Extracellular α-synuclein oligomers modulate synaptic transmission and impair LTP via NMDA-receptor activation. J. Neurosci. 32: 11750-11762.
60. Angot, E., J.A. Steiner, C.M. Tom, et al. 2012. Alpha-synuclein cell-to-cell transfer and seeding in grafted dopaminergic neurons in vivo. PLoS One 7: e39465.
61. Narkiewicz, J., G Giachin & G. Legname . 2014. In vitro aggregation assays for the characterization of α-synuclein prion-like properties. Prion 8: 1-14.
62. Mougenot, A., S. Nicot, A. Bencsik, et al. 2012. Prion-like acceleration of a synucleinopathy in a transgenic mouse model. Neurobiol. Aging 33: 2225-2228.
63. Luk, K.C., V. Kehm, J. Carroll, et al. 2012. Pathological α-synuclein transmission initiates Parkinson-like neurodegeneration in nontransgenic mice. Science 338: 949-953.
64. Löw, K & P. Aebischer . 2012. Use of viral vectors to create animal models for Parkinson's disease. Neurobiol. Dis. 48: 189-201.
65. Lo Bianco, C., J.-L. Ridet, B.L., Schneider, et al. 2002. α-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.
66. Gruden, M.A., T V. Davydova, V.B. Narkevich, et al. 2014. Intranasal administration of α-synuclein aggregates: a Parkinson's disease model with behavioral and neurochemical correlates. Behav. Brain Res. 263: 158-168.
67. Breydo, L., J.W. Wu & V.N. Uversky . 2012. Α-synuclein misfolding and Parkinson's disease. Biochim. Biophys. Acta 1822: 261-285.
68. Chen, L., M. Periquet, X. Wang, et al. 2009. Tyrosine and serine phosphorylation of α-synuclein have opposing effects on neurotoxicity and soluble oligomer formation. J. Clin. Invest. 119: 3257-3265.
69. Di Fonzo, A., C.F. Rohe, J. Ferreira, et al. 2005. A frequent LRRK2 gene mutation associated with autosomal dominant Parkinson's disease. Lancet 365: 412-415.
70. Bonifati, V. 2007. LRRK2 low-penetrance mutations (Gly2019Ser) and risk alleles (Gly2385Arg)-linking familial and sporadic Parkinson's disease. Neurochem. Res. 32: 1700-1708.
71. Marsh, M & H.T. McMahon . 1999. The structural era of endocytosis. Science 285: 215-220.
72. Fernandes, A.C., J., Slabbaert, S. Kuenen, et al. 2010. Identification of novel genes involved in synaptic communication. J. Neurogenet. 24: 42.
73. Hernandez, D., C. Paisan Ruiz, A. Crawley, et al. 2005. The dardarin G 2019 S mutation is a common cause of Parkinson's disease but not other neurodegenerative diseases. Neurosci. Lett. 389: 137-139.
74. Giasson, B.I., J.P. Covy, N.M. Bonini, et al. 2006. Biochemical and pathological characterization of Lrrk2. Ann. Neurol. 59: 315-322.
75. Ross, O.A., M. Toft, A.J. Whittle, et al. 2006. Lrrk2 and Lewy body disease. Ann. Neurol. 59: 388-393.
76. Li, Y., W. Liu, T.F. Oo, et al. 2009. Mutant LRRK2(R1441G) BAC transgenic mice recapitulate cardinal features of Parkinson's disease. Nat. Neurosci. 12: 826-828.
77. Li, X., J.C. Patel, J. Wang, 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.
78. Ramonet, D., J.P.L. Daher, B.M. Lin, et al. 2011. Dopaminergic neuronal loss, reduced neurite complexity and autophagic abnormalities in transgenic mice expressing G2019S mutant LRRK2. PLoS One 6: e18568.
79. Lee, S.B., W., Kim, S. Lee, et al. 2007. Loss of LRRK2/PARK8 induces degeneration of dopaminergic neurons in Drosophila. Biochem. Biophys. Res. Commun. 358: 534-539.
80. Hindle, S.J. & C.J.H. Elliott . 2013. Spread of neuronal degeneration in a dopaminergic, Lrrk-G2019S model of Parkinson disease. Autophagy 9: 936-968.
81. Farsad, K., N. Ringstad, K. Takei, et al. 2001. Generation of high curvature membranes mediated by direct endophilin bilayer interactions. J. Cell Biol. 155: 193-200.
82. Ambroso, M.R., B.G. Hegde & R. Langen . 2014. Endophilin A1 induces different membrane shapes using a conformational switch that is regulated by phosphorylation. Proc. Natl. Acad. Sci. U. S. A. 111: 6982-7.
83. Martin, I., J.W. Kim, B.D. Lee, et al. 2014. Ribosomal protein s15 phosphorylation mediates LRRK2 neurodegeneration in Parkinson's disease. Cell 157: 472-485.
84. Gehrke, S., Y. Imai, N. Sokol, et al. 2010. Pathogenic LRRK2 negatively regulates microRNA-mediated translational repression. Nature 466: 637-641.
85. Russo, I., L Bubacco & E. Greggio . 2014. LRRK2 and neuroinflammation: partners in crime in Parkinson's disease? J. Neuroinflammation 11: 52.
86. Orenstein, S.J., S.-H., Kuo, I. Tasset, et al. 2013. Interplay of LRRK2 with chaperone-mediated autophagy. Nat. Neurosci. 16: 394-406.
87. Alegre-Abarrategui, J., H., Christian, MM.P., Lufino, et al. 2009. LRRK2 regulates autophagic activity and localizes to specific membrane microdomains in a novel human genomic reporter cellular model. Hum. Mol. Genet. 18: 4022-4034.
88. Abeliovich, A., Y. Schmitz, I. Fariñas, et al. 2000. Mice lacking α-synuclein display functional deficits in the nigrostriatal dopamine system. Neuron 25: 239-252.
89. McNaught, K.S., C.W., Olanow, B. Halliwell, et al. 2001. Failure of the ubiquitin-proteasome system in Parkinson's disease. Nat. Rev. Neurosci. 2: 589-594.
90. Cuervo, A.M. & E. Wong . 2014. Chaperone-mediated autophagy: roles in disease and aging. Cell Res. 24: 92-104.
91. Janda, E., C. Isidoro, C. Carresi, et al. 2012. Defective autophagy in Parkinson's disease: role of oxidative stress. Mol. Neurobiol. 46: 639-661.
92. Spencer, B., R. Potkar, M. Trejo, et al. 2009. Beclin 1 gene transfer activates autophagy and ameliorates the neurodegenerative pathology in α-synuclein models of Parkinson's and Lewy body diseases. J. Neurosci. 29: 13578-13588.
93. Floto, R.A., S., Sarkar, S.L., Schreiber, et al. 2007. Small molecule enhancers of rapamycin-induced TOR inhibition promote autophagy, reduce toxicity in Huntington's disease models and enhance killing of mycobacteria by macrophages. Autophagy 3-6: 620-622.
94. Bae, E.-J., H.-J., Lee, E. Rockenstein, et al. 2012. Antibody-aided clearance of extracellular α-synuclein prevents cell-to-cell aggregate transmission. J. Neurosci. 32: 13454-13469.
95. Masliah, E., E. Rockenstein, M. Mante, et al. 2011. Passive immunization reduces behavioral and neuropathological deficits in an α-synuclein transgenic model of Lewy body disease. PLoS One 6: e19338.
96. Valera, E & E. Masliah . 2013. Immunotherapy for neurodegenerative diseases: focus on α-synucleinopathies. Pharmacol. Ther. 138: 311-322.
97. Tran, H.T., C.H.-Y. Chung, M. Iba, et al. 2014. Α-synuclein immunotherapy blocks uptake and templated propagation of misfolded α-synuclein and neurodegeneration. Cell Rep. 7: 2054-2065.
98. Simuni, T & H. Hurtig . 2002. "Levodopa: 30 years in progress." In Parkinson's Disease: Diagnosis and Clinical Management. S. Factor & W. Weiner, Eds. New York: Demos Medical Publishing.
99. Brand, M.D., A.L. Orr, I.V. Perevoshchikova, et al. 2013. The role of mitochondrial function and cellular bioenergetics in ageing and disease. Br. J. Dermatol. 169: 1-8.
100. Gorman, a M., S. Ceccatelli & S. Orrenius . 2000. Role of mitochondria in neuronal apoptosis. Dev. Neurosci. 22: 348-358.
101. Verstreken, P., C.V. Ly, K.J.T. Venken, et al. 2005. Synaptic mitochondria are critical for mobilization of reserve pool vesicles at Drosophila neuromuscular junctions. Neuron 47: 365-378.
102. Vos, M., E. Lauwers & P. Verstreken . 2010. Synaptic mitochondria in synaptic transmission and organization of vesicle pools in health and disease. Front. Synaptic Neurosci. 2: 139.
103. Kitada, T., S. Asakawa, N. Hattori, et al. 1998. Mutations in the Parkin gene cause autosomal recessive juvenile parkinsonism. Nature 392: 605-608.
104. Valente, E.M., P.M. Abou-Sleiman, V. Caputo, et al. 2004. Hereditary early-onset Parkinson's disease caused by mutations in PINK1. Science 304: 1158-1160.
105. Bonifati, V., P. Rizzu, M.J. van Baren, et al. 2003. Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism. Science 299: 256-259.
106. Trevor, A.J., N Castagnoli & TP. Singer . 1988. The formation of reactive intermediates in the MAO-catalyzed oxidation of the nigrostriatal toxin 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP). Toxicology 49: 513-519.
107. Johannessen, J.N., C.C. Chiueh, R.S. Burns, et al. 1985. IV. Differences in the metabolism of MPTP in the rodent and primate parallel differences in sensitivity to its neurotoxic effects. Life Sci. 36: 219-224.
108. Sonsalla, P.K. & R.E. Heikkila . 1988. Neurotoxic effects of 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) and methamphetamine in several strains of mice. Prog. Neuropsychopharmacol. Biol. Psychiatry 12: 345-354.
109. Donnan, G.A., G.L. Willis, S.J. Kaczmarczyk, et al. 1987. Motor function in the 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine-treated mouse. J. Neurol. Sci. 77: 185-191.
110. Meredith, G.E., S. Totterdell, E. Petroske, et al. 2002. Lysosomal malfunction accompanies α-synuclein aggregation in a progressive mouse model of Parkinson's disease. Brain Res. 956: 156-165.
111. Fornai, F., O.M. Schlüter, P. Lenzi, et al. 2005. Parkinson-like syndrome induced by continuous MPTP infusion: convergent roles of the ubiquitin-proteasome system and α-synuclein. Proc. Natl. Acad. Sci. U. S. A. 102: 3413-3418.
112. Shimoji, M., L. Zhang, A.S. Mandir, et al. 2005. Absence of inclusion body formation in the MPTP mouse model of Parkinson's disease. Brain Res. Mol. Brain Res. 134: 103-108.
113. Jackson-Lewis, V & S. Przedborski . 2007. Protocol for the MPTP mouse model of Parkinson's disease. Nat. Protoc. 2: 141-151.
114. Sonsalla, P.K., G.D. Zeevalk & D.C. German . 2008. Chronic intraventricular administration of 1-methyl-4-phenylpyridinium as a progressive model of Parkinson's disease. Parkinsonism Relat. Disord. 14(Suppl 2): S116-S118.
115. Porras, G., Q. Li & E. Bezard . 2012. Modeling Parkinson's disease in primates: the MPTP model. Cold Spring Harb. Perspect. Med. 2: a009308.
116. Schneider, J.S., A. Yuwiler & C.H. Markham . 1987. Selective loss of subpopulations of ventral mesencephalic dopaminergic neurons in the monkey following exposure to MPTP. Brain Res. 411: 144-150.
117. Burns, R.S., C.C. Chiueh, S.P. Markey, et al. 1983. A primate model of parkinsonism: selective destruction of dopaminergic neurons in the pars compacta of the Substantia nigra by N-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine. Proc. Natl. Acad. Sci. U. S. A. 80: 4546-4550.
118. Xiong, N., X. Long, J. Xiong, et al. 2012. Mitochondrial complex, I inhibitor rotenone-induced toxicity and its potential mechanisms in Parkinson's disease models. Crit. Rev. Toxicol. 42: 613-632.
119. Alam, M & W.J. Schmidt . 2002. Rotenone destroys dopaminergic neurons and induces parkinsonian symptoms in rats. Behav. Brain Res. 136: 317-324.
120. Betarbet, R., T.B. Sherer, G. MacKenzie, et al. 2000. Chronic systemic pesticide exposure reproduces features of Parkinson's disease. Nat. Neurosci. 3: 1301-1306.
121. Coulom, H & S. Birman . 2004. Chronic exposure to rotenone models sporadic Parkinson's disease in Drosophila melanogaster. J. Neurosci. 24: 10993-10998.
122. Sherer, T.B., J.H. Kim, R. Betarbet, et al. 2003. Subcutaneous rotenone exposure causes highly selective dopaminergic degeneration and α-synuclein aggregation. Exp. Neurol. 179: 9-16.
123. Inden, M., Y. Kitamura, M. Abe, et al. 2011. Parkinsonian rotenone mouse model: reevaluation of long-term administration of rotenone in C57BL/6 mice. Biol. Pharm. Bull. 34: 92-96.
124. Testa, C.M., T.B. Sherer & J.T. Greenamyre . 2005. Rotenone induces oxidative stress and dopaminergic neuron damage in organotypic Substantia nigra cultures. Brain Res. Mol. Brain Res. 134: 109-118.
125. Radad, K., W.-D. Rausch & G. Gille . 2006. Rotenone induces cell death in primary dopaminergic culture by increasing ROS production and inhibiting mitochondrial respiration. Neurochem. Int. 49: 379-386.
126. Esteve-Rudd, J., L. Fernández-Sánchez, P. Lax, et al. 2011. Rotenone induces degeneration of photoreceptors and impairs the dopaminergic system in the rat retina. Neurobiol. Dis. 44: 102-115.
127. Bindoff, L.A., M.A. Birch-Machin, N.E.F. Cartlidge, et al. 1991. Respiratory chain abnormalities in skeletal muscle from patients with Parkinson' s disease. J. Neurol. Sci. 104: 203-208.
128. Haas, R.H., F. Nasirian, K. Nakano, et al. 1995. Low platelet mitochondrial complex I and complex II/III activity in early untreated Parkinson's disease. Ann. Neurol. 37: 714-722.
129. Giovannini, P., I. Piccolo, S. Genitrini, et al. 1991. Early-onset Parkinson's disease. Mov. Disord. 6: 36-42.
130. Scarffe, L.A., D.A. Stevens, V.L. Dawson, et al. 2014. Parkin and PINK1: much more than mitophagy. Trends Neurosci. 37: 315-324.
131. Winklhofer, KF. 2014. Parkin and mitochondrial quality control: toward assembling the puzzle. Trends Cell Biol. 24: 332-341.
132. Shimura, H., N. Hattori, S. Kubo, et al. 2000. Familial Parkinson disease gene product, Parkin, is a ubiquitin-protein ligase. Nat. Genet. 25: 302-305.
133. LaVoie, M.J., B.L. Ostaszewski, A. Weihofen, et al. 2005. Dopamine covalently modifies and functionally inactivates Parkin. Nat. Med. 11: 1214-1221.
134. Goldberg, M.S., S.M. Fleming, J.J. Palacino, et al. 2003. Parkin-deficient mice exhibit nigrostriatal deficits but not loss of dopaminergic neurons. J. Biol. Chem. 278: 43628-43635.
135. Perez, F.A. & R.D. Palmiter . 2005. Parkin-deficient mice are not a robust model of parkinsonism. Proc. Natl. Acad. Sci. U. S. A. 102: 2174-2179.
136. Von Coelln, R., B. Thomas, J.M. Savitt, et al. 2004. Loss of locus coeruleus neurons and reduced startle in Parkin null mice. Proc. Natl. Acad. Sci. 101: 10744-10749.
137. Shin, J.-H., H.S. Ko, H. Kang, et al. 2011. PARIS (ZNF746) repression of PGC-1α contributes to neurodegeneration in Parkinson's disease. Cell 144: 689-702.
138. Lu, X.-H., S.M. Fleming, B. Meurers, 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 α-synuclein. J. Neurosci. 29: 1962-1976.
139. Cha, G.-H., S. Kim, J. Park, et al. 2005. Parkin negatively regulates JNK pathway in the dopaminergic neurons of Drosophila. Proc. Natl. Acad. Sci. U. S. A. 102: 10345-10350.
140. Greene, J.C., A.J. Whitworth, I. Kuo, et al. 2003. Mitochondrial pathology and apoptotic muscle degeneration in Drosophila Parkin mutants. Proc. Natl. Acad. Sci. U. S. A. 100: 4078-4083.
141. Whitworth, A.J., D.A. Theodore, J.C. Greene, et al. 2005. Increased glutathione S-transferase activity rescues dopaminergic neuron loss in a Drosophila model of Parkinson's disease. Proc. Natl. Acad. Sci. U. S. A. 102: 8024-8029.
142. Clark, I.E., M.W. Dodson, C. Jiang, et al. 2006. Drosophila pink1 is required for mitochondrial function and interacts genetically with Parkin. Nature 441: 1162-1166.
143. Park, J., S.B. Lee, S. Lee, et al. 2006. Mitochondrial dysfunction in Drosophila PINK1 mutants is complemented by Parkin. Nature 441: 1157-1161.
144. Vilain, S., G. Esposito, D. Haddad, et al. 2012. The yeast complex I equivalent NADH dehydrogenase rescues pink1 mutants. PLoS Genet. 8: e1002456.
145. Vos, M., G. Esposito, J.N. Edirisinghe, et al. 2012. Vitamin K2 is a mitochondrial electron carrier that rescues pink1 deficiency. Science 336: 1306-1310.
146. Palacino, J.J., D. Sagi, M.S. Goldberg, et al. 2004. Mitochondrial dysfunction and oxidative damage in Parkin-deficient mice. J. Biol. Chem. 279: 18614-18622.
147. Vincent, A., L. Briggs, G.F.J. Chatwin, et al. 2012. Parkin-induced defects in neurophysiology and locomotion are generated by metabolic dysfunction and not oxidative stress. Hum. Mol. Genet. 21: 1760-1769.
148. Narendra, D., A. Tanaka, D.-F. Suen, et al. 2008. Parkin is recruited selectively to impaired mitochondria and promotes their autophagy. J. Cell Biol. 183: 795-803.
149. Chan, N.C., A.M. Salazar, A.H. Pham, et al. 2011. Broad activation of the ubiquitin-proteasome system by Parkin is critical for mitophagy. Hum. Mol. Genet. 20: 1726-1737.
150. Poole, A.C., R.E. Thomas, S. Yu, et al. 2010. The mitochondrial fusion-promoting factor mitofusin is a substrate of the PINK1/Parkin pathway. PLoS One 5: e10054.
151. Yoshii, S.R., C. Kishi, N. Ishihara, et al. 2011. Parkin mediates proteasome-dependent protein degradation and rupture of the outer mitochondrial membrane. J. Biol. Chem. 286: 19630-19640.
152. Ziviani, E., R.N. Tao & A.J. Whitworth . 2010. Drosophila Parkin requires PINK1 for mitochondrial translocation and ubiquitinates mitofusin. Proc. Natl. Acad. Sci. U. S. A. 107: 5018-5023.
153. Haddad, D.M., S. Vilain, M. Vos, et al. 2013. Mutations in the intellectual disability gene Ube2a cause neuronal dysfunction and impair Parkin-dependent mitophagy. Mol. Cell 50: 831-843.
154. Cornelissen, T., D. Haddad, F. Wauters, et al. 2014. The deubiquitinase USP15 antagonizes Parkin-mediated mitochondrial ubiquitination and mitophagy. Hum. Mol. Genet. 23: 5227-5242.
155. Bingol, B., J.S., Tea, L. Phu, et al. 2014. The mitochondrial deubiquitinase USP30 opposes Parkin-mediated mitophagy. Nature 509: 370-375.
156. Corti, O., C. Hampe, H. Koutnikova, et al. 2003. The p38 subunit of the aminoacyl-tRNA synthetase complex is a Parkin substrate: linking protein biosynthesis and neurodegeneration. Hum. Mol. Genet. 12: 1427-1437.
157. Lee, Y., S.S., Karuppagounder, J.-H., Shin, et al. 2013. Parthanatos mediates AIMP2-activated age-dependent dopaminergic neuronal loss. Nat. Neurosci. 16: 1392-1400.
158. Kitada, T., A., Pisani, D.R., Porter, et al. 2007. Impaired dopamine release and synaptic plasticity in the striatum of PINK1-deficient mice. Proc. Natl. Acad. Sci. 104: 11441-11446.
159. Morais, V.A., P., Verstreken, A. Roethig, et al. 2009. Parkinson's disease mutations in PINK1 result in decreased Complex I activity and deficient synaptic function. EMBO Mol. Med. 1: 99-111.
160. Gautier, C.A., T. Kitada & J. Shen . 2008. Loss of PINK1 causes mitochondrial functional defects and increased sensitivity to oxidative stress. Proc. Natl. Acad. Sci. U. S. A. 105: 11364-11369.
161. Esposito, G., M. Vos, S. Vilain, et al. 2013. Aconitase causes iron toxicity in Drosophila pink1 mutants. PLoS Genet. 9: e1003478.
162. Yang, Y., S. Gehrke, Y. Imai, et al. 2006. Mitochondrial pathology and muscle and dopaminergic neuron degeneration caused by inactivation of Drosophila Pink1 is rescued by Parkin. Proc. Natl. Acad. Sci. U. S. A. 103: 10793-10798.
163. Liu, W., Acín-R. Peréz, K.D. Geghman, et al. 2011. Pink1 regulates the oxidative phosphorylation machinery via mitochondrial fission. Proc. Natl. Acad. Sci. U. S. A. 108: 12920-12924.
164. Klein, P., Müller-A.K. Rischart, E. Motori, et al. 2014. Ret rescues mitochondrial morphology and muscle degeneration of Drosophila Pink1 mutants. EMBO J. 33: 341-355.
165. Morais, V.A., D. Haddad, K. Craessaerts, et al. 2014. PINK1 loss-of-function mutations affect mitochondrial complex I activity via NdufA10 ubiquinone uncoupling. Science 344: 203-207.
166. Vos, M., B. Lovisa, A. Geens, et al. 2013. Near-infrared 808 nm light boosts complex IV-dependent respiration and rescues a Parkinson-related pink1 model. PLoS One 8: e78562.
167. Martin, I., V.L. Dawson & TM. Dawson . 2011. Recent advances in the genetics of Parkinson's disease. Annu Rev Genomics Hum Genet 12: 301-325.
168. Meulener, M.C., K. Xu, L. Thomson, et al. 2006. Mutational analysis of DJ-1 in Drosophila implicates functional inactivation by oxidative damage and aging. Proc. Natl. Acad. Sci. 103: 12517-12522.
169. Moore, D.J., L. Zhang, J. Troncoso, et al. 2005. Association of DJ-1 and Parkin mediated by pathogenic DJ-1 mutations and oxidative stress. Hum. Mol. Genet. 14: 71-84.
170. Olzmann, J.A., K. Brown, K.D. Wilkinson, et al. 2004. Familial Parkinson's disease-associated L166P mutation disrupts DJ-1 protein folding and function. J. Biol. Chem. 279: 8506-8515.
171. Rousseaux M.W.C., P.C. Marcogliese, D. Qu, et al. 2012. Progressive dopaminergic cell loss with unilateral-to-bilateral progression in a genetic model of Parkinson disease. Proc. Natl. Acad. Sci. 109: 15918-15923.
172. Hao, L., B.I. Giasson & N.M. Bonini . 2010. DJ-1 is critical for mitochondrial function and rescues PINK1 loss of function. Proc. Natl. Acad. Sci. U. S. A. 107: 9747-9752.
173. Tomac, A., E. Lindqvist, L.F. Lin, et al. 1995. Protection and repair of the nigrostriatal dopaminergic system by GDNF in vivo. Nature 373: 335-339.
174. Gash, D.M., Z. Zhang, A. Ovadia, et al. 1996. Functional recovery in parkinsonian monkeys treated with GDNF. Nature 380: 252-255.
175. Ko, H.S., Y. Lee, J.-H., Shin, et al. 2010. Phosphorylation by the c-Abl protein tyrosine kinase inhibits Parkin's ubiquitination and protective function. Proc. Natl. Acad. Sci. U. S. A. 107: 16691-16696.
176. Karuppagounder, S.S., S. Brahmachari, Y. Lee, et al. 2014. The c-Abl inhibitor, nilotinib, protects dopaminergic neurons in a preclinical animal model of Parkinson's disease. Sci. Rep. 4: 4874.
177. Imam, S.Z., Q. Zhou, A. Yamamoto, et al. 2011. Novel regulation of Parkin function through c-Abl-mediated tyrosine phosphorylation: implications for Parkinson's disease. J. Neurosci. 31: 157-163.
178. Larsen, C.N., B. a. Krantz & KD. Wilkinson . 1998. Substrate specificity of deubiquitinating enzymes: ubiquitin C-terminal hydrolases. Biochemistry 37: 3358-3368.
179. Liu, Y., L. Fallon, H.A. Lashuel, et al. 2002. The UCH-L1 gene encodes two opposing enzymatic activities that affect α-synuclein degradation and Parkinson's disease susceptibility. Cell 111: 209-218.
180. Wilkinson, K.D., K. Lee, S. Deshpande, et al. 1989. The neuron-specific protein PGP 9.5 is a ubiquitin carboxyl-terminal hydrolase. Science 246: 670-673.
181. Leroy, E., R. Boyer, G. Auburger, et al. 1998. The ubiquitin pathway in Parkinson's disease. Nature 395: 451-452.
182. Kurihara, L.J., T. Kikuchi, K. Wada, et al. 2001. Loss of Uch-L1 and Uch-L3 leads to neurodegeneration, posterior paralysis and dysphagia. Hum. Mol. Genet. 10: 1963-1970.
183. Chen, F., Y. Sugiura, K.G., Myers, et al. 2010. Ubiquitin carboxyl-terminal hydrolase L1 is required for maintaining the structure and function of the neuromuscular junction. Proc. Natl. Acad. Sci. U. S. A. 107: 1636-1641.
184. Kabuta, T., A. Furuta, S. Aoki, et al. 2008. Aberrant interaction between Parkinson disease-associated mutant UCH-L1 and the lysosomal receptor for chaperone-mediated autophagy. J. Biol. Chem. 283: 23731-23738.
185. Yasuda, T., T. Nihira, Y.-R. Ren, et al. 2009. Effects of UCH-L1 on α-synuclein over-expression mouse model of Parkinson's disease. J. Neurochem. 108: 932-944.
186. Shimshek, D.R., T. Schweizer, P. Schmid, et al. 2012. Excess α-synuclein worsens disease in mice lacking ubiquitin carboxy-terminal hydrolase L1. Sci. Rep. 2: 262.
187. Zhou, Y., G. Gu, D.R. Goodlett, et al. 2004. Analysis of α-synuclein-associated proteins by quantitative proteomics. J. Biol. Chem. 279: 39155-39164.
188. Dehay, B., A. Ramirez, M. Martinez-Vicente, et al. 2012. Loss of P-type ATPase ATP13A2/PARK9 function induces general lysosomal deficiency and leads to Parkinson disease neurodegeneration. Proc. Natl. Acad. Sci. U. S. A. 109: 9611-9616.
189. Schultheis, P.J., S.M. Fleming, A.K. Clippinger, 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.
190. Ramirez, A., A. Heimbach, J. Gründemann, et al. 2006. Hereditary parkinsonism with dementia is caused by mutations in ATP13A2, encoding a lysosomal type 5 P-type ATPase. Nat. Genet. 38: 1184-1191.
191. Gitler, A.D., A. Chesi, M.L. Geddie, et al. 2009. α-Synuclein is part of a diverse and highly conserved interaction network that includes PARK9 and manganese toxicity. Nat. Genet. 41: 308-315.
192. Vande Walle, L. M. Lamkanfi & P. Vandenabeele . 2008. The mitochondrial serine protease HtrA2/Omi: an overview. Cell Death Differ. 15: 453-460.
193. Strauss, K.M., L.M. Martins, H. Plun-Favreau, et al. 2005. Loss of function mutations in the gene encoding Omi/HtrA2 in Parkinson's disease. Hum. Mol. Genet. 14: 2099-2111.
194. Plun-Favreau, H., K. Klupsch, N. Moisoi, et al. 2007. The mitochondrial protease HtrA2 is regulated by Parkinson's disease-associated kinase PINK1. Nat. Cell Biol. 9: 1243-1252.
195. Martins, L.M., A. Morrison, K. Klupsch, et al. 2004. Neuroprotective role of the reaper-related serine protease HtrA2/Omi revealed by targeted deletion in mice. Mol. Cell. Biol. 24: 9848-9862.
196. Moisoi, N., K. Klupsch, V. Fedele, et al. 2009. Mitochondrial dysfunction triggered by loss of HtrA2 results in the activation of a brain-specific transcriptional stress response. Cell Death Differ. 16: 449-464.
197. Tain, L.S., R.B. Chowdhury, R.N. Tao, et al. 2009. Drosophila HtrA2 is dispensable for apoptosis but acts downstream of PINK1 independently from Parkin. Cell Death Differ. 16: 1118-1125.
198. Krebs, C.E., S. Karkheiran, J.C. Powell, et al. 2013. The Sac1 domain of SYNJ1 identified mutated in a family with early-onset progressive Parkinsonism with generalized seizures. Hum. Mutat. 34: 1200-1207.
199. Quadri, M., M. Fang, M. Picillo, et al. 2013. Mutation in the SYNJ1 gene associated with autosomal recessive, early-onset Parkinsonism. Hum. Mutat. 34: 1208-1215.
200. Cremona, O., G. Di Paolo, M.R. Wenk, et al. 1999. Essential role of phosphoinositide metabolism in synaptic vesicle recycling. Cell 99: 179-188.
201. Harris, T.W., E. Hartwieg, H.R. Horvitz, et al. 2000. Mutations in synaptojanin disrupt synaptic vesicle recycling. J. Cell Biol. 150: 589-600.
202. Verstreken, P., T.W. Koh, K.L. Schulze, et al. 2003. Synaptojanin is recruited by endophilin to promote synaptic vesicle uncoating. Neuron 40: 733-748.
203. Neumann, J., J. Bras, E. Deas, et al. 2009. Glucocerebrosidase mutations in clinical and pathologically proven Parkinson's disease. Brain 132: 1783-1794.
204. Beutler, E., a. Demina & T. Gelbart . 1994. Glucocerebrosidase mutations in Gaucher disease. Mol. Med. 1: 82-92.
205. Kono, S., K. Shirakawa, Y. Ouchi, et al. 2007. Dopaminergic neuronal dysfunction associated with parkinsonism in both a Gaucher disease patient and a carrier. J. Neurol. Sci. 252: 181-184.
206. Manning-Boğ, A.B., B. Schüle & J.W. Langston . 2009. α-Synuclein-glucocerebrosidase interactions in pharmacological Gaucher models: a biological link between Gaucher disease and parkinsonism. Neurotoxicology 30: 1127-1132.
207. Morin, N., V. a. Jourdain & T. Di Paolo . 2014. Modeling dyskinesia in animal models of Parkinson disease. Exp. Neurol. 256: 105-116.
208. Duty, S. & P. Jenner . 2011. Animal models of Parkinson's disease: a source of novel treatments and clues to the cause of the disease. Br. J. Pharmacol. 164: 1357-1391.
209. Snow, B.J., F.L. Rolfe, M.M. Lockhart, et al. 2010. A double-blind, placebo-controlled study to assess the mitochondria-targeted antioxidant MitoQ as a disease-modifying therapy in Parkinson's disease. Mov. Disord. 25: 1670-1674.
210. Ye, Z., E. Altena, C. Nombela, et al. 2014. Improving response inhibition in Parkinson's disease with atomoxetine. Biol. Psychiatry 1-8. doi:10.1016/j.biopsych.2014.01.024