Animal models of α-synucleinopathy for Parkinson disease drug development

Key Points

  • Several classes of mammalian models of α-synucleinopathy are available for use in drug development. These include transgenic models and models based on delivery of α-synuclein protein (such as preformed fibrils (PFFs) or extracts of Lewy bodies from post-mortem human tissue) or α-synuclein-encoding genes (for example, using adeno-associated viruses (AAVs)).

  • These models are being applied to assess efficacy, inform dosing and define therapeutic windows of potential new treatments.

  • The AAV models stand out as drug development platforms as, to date, they are robust and amenable to medium-throughput evaluation and can be used in multiple species from mouse to rat to non-human primate (NHP). The transgenic and PFF models may prove important for longer-term evaluation of evolving symptoms and for examining pathology in multiple systems, whereas the Lewy extract models are not in a position for widespread use, as patient material will differ between experiments, and duration to reach end points, so far, exceeds a time frame for relatively rapid screening of candidates.

  • AAV NHP models are especially well suited as a final stage before initiating clinical development, not only for evaluating the efficacy of a treatment and the clinically relevant measures of target engagement, but also for defining the therapeutic index of a candidate in a species best able to predict effects anticipated in human.

  • Navigating the choice of different models available is often difficult. However, with the understanding of the mechanism of action of the proposed treatment, along with consideration of potential species interactions, one can now rationally define a development plan that uses available models most optimally to advance through the preclinical space.

Abstract

A major challenge in Parkinson disease (PD) will be to turn an emerging and expanding pipeline of novel disease-modifying candidate compounds into therapeutics. Novel targets need in vivo validation, and candidate therapeutics require appropriate preclinical platforms on which to define potential efficacy and target engagement before advancement to clinical development. We propose that α-synuclein (α-syn)-based mammalian models will be crucial for this process. Here, we review α-syn transgenic mouse models, viral vector models of α-syn overexpression and models of 'prion-like' spread of α-syn, and describe how each of these model types may contribute to PD drug discovery. We conclude by presenting our opinion on how to use a combination of these models through the late-stage preclinical, proof-of-principle investigation of novel therapeutics.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Proposed physiological and pathological roles of α-synuclein.
Figure 2: Identification of potential disease-modifying action: a logic flow chart.

References

  1. 1

    Pringsheim, T., Jette, N., Frolkis, A. & Steeves, T. D. The prevalence of Parkinson's disease: a systematic review and meta-analysis. Mov. Disord. 29, 1583–1590 (2014).

    PubMed  Google Scholar 

  2. 2

    Kalia, L. V. & Lang, A. E. Parkinson's disease. Lancet 386, 896–912 (2015).

    CAS  Google Scholar 

  3. 3

    Spillantini, M. G. et al. α-Synuclein in Lewy bodies. Nature 388, 839–840 (1997).

    CAS  PubMed  Google Scholar 

  4. 4

    Schneider, J. S. et al. GM1 ganglioside in Parkinson's disease: pilot study of effects on dopamine transporter binding. J. Neurol. Sci. 356, 118–123 (2015).

    CAS  PubMed Central  PubMed  Google Scholar 

  5. 5

    Schneider, J. S., Seyfried, T. N., Choi, H. S. & Kidd, S. K. Intraventricular sialidase administration enhances GM1 ganglioside expression and is partially neuroprotective in a mouse model of Parkinson's disease. PLoS ONE 10, e0143351 (2015). This study provides early preclinical support for the current clinical development of GM1 ganglioside for disease modification in PD.

    PubMed Central  PubMed  Google Scholar 

  6. 6

    Guo, J. F. et al. Involvement of Bcl-2-associated athanogene (BAG)-family proteins in the neuroprotection by rasagiline. Int. J. Clin. Exp. Med. 8, 18158–18164 (2015).

    CAS  PubMed Central  PubMed  Google Scholar 

  7. 7

    Mandel, S. A., Sagi, Y. & Amit, T. Rasagiline promotes regeneration of substantia nigra dopaminergic neurons in post-MPTP-induced Parkinsonism via activation of tyrosine kinase receptor signaling pathway. Neurochem. Res. 32, 1694–1699 (2007).

    CAS  PubMed  Google Scholar 

  8. 8

    Eriksen, J. L., Dawson, T. M., Dickson, D. W. & Petrucelli, L. Caught in the act: α-synuclein is the culprit in Parkinson's disease. Neuron 40, 453–456 (2003).

    CAS  PubMed  Google Scholar 

  9. 9

    Falkenburger, B. H., Saridaki, T. & Dinter, E. Cellular models for Parkinson's disease. J. Neurochem. 139 (Suppl. 1), 121–130 (2016).

    CAS  PubMed  Google Scholar 

  10. 10

    Javed, H., Kamal, M. A. & Ojha, S. An overview on the role of α-synuclein in experimental models of Parkinson's disease from pathogenesis to therapeutics. CNS Neurol. Disord. Drug Targets 15, 1240–1252 (2016).

    CAS  PubMed  Google Scholar 

  11. 11

    Peelaerts, W. & Baekelandt, V. α-Synuclein strains and the variable pathologies of synucleinopathies. J. Neurochem. 139 (Suppl. 1), 256–274 (2016).

    CAS  PubMed  Google Scholar 

  12. 12

    Luth, E. S., Bartels, T., Dettmer, U., Kim, N. C. & Selkoe, D. J. Purification of α-synuclein from human brain reveals an instability of endogenous multimers as the protein approaches purity. Biochemistry 54, 279–292 (2015).

    CAS  PubMed  Google Scholar 

  13. 13

    Logan, T., Bendor, J., Toupin, C., Thorn, K. & Edwards, R. H. α-Synuclein promotes dilation of the exocytotic fusion pore. Nat. Neurosci. 20, 681–689 (2017).

    CAS  PubMed Central  PubMed  Google Scholar 

  14. 14

    Abeliovich, A. et al. Mice lacking α-synuclein display functional deficits in the nigrostriatal dopamine system. Neuron 25, 239–252 (2000).

    CAS  PubMed  Google Scholar 

  15. 15

    Chandra, S. et al. Double-knockout mice for α- and β-synucleins: effect on synaptic functions. Proc. Natl Acad. Sci. USA 101, 14966–14971 (2004).

    CAS  PubMed  Google Scholar 

  16. 16

    Greten-Harrison, B. et al. αβγ-synuclein triple knockout mice reveal age-dependent neuronal dysfunction. Proc. Natl Acad. Sci. USA 107, 19573–19578 (2010).

    CAS  PubMed  Google Scholar 

  17. 17

    Burre, J. et al. α-Synuclein promotes SNARE-complex assembly in vivo and in vitro. Science 329, 1663–1667 (2010).

    CAS  PubMed Central  PubMed  Google Scholar 

  18. 18

    Choi, B. K. et al. Large α-synuclein oligomers inhibit neuronal SNARE-mediated vesicle docking. Proc. Natl Acad. Sci. USA 110, 4087–4092 (2013).

    CAS  PubMed  Google Scholar 

  19. 19

    Lundblad, M., Decressac, M., Mattsson, B. & Bjorklund, A. Impaired neurotransmission caused by overexpression of α-synuclein in nigral dopamine neurons. Proc. Natl Acad. Sci. USA 109, 3213–3219 (2012). This study uses in vivo amperometry to measure dopamine changes in the striatum and shows that α-syn is involved in synaptic dopamine release in the basal ganglia.

    CAS  Google Scholar 

  20. 20

    Taylor, T. N. et al. Region-specific deficits in dopamine, but not norepinephrine, signaling in a novel A30P α-synuclein BAC transgenic mouse. Neurobiol. Dis. 62, 193–207 (2014).

    CAS  PubMed Central  PubMed  Google Scholar 

  21. 21

    Platt, N. J., Gispert, S., Auburger, G. & Cragg, S. J. Striatal dopamine transmission is subtly modified in human A53Tα-synuclein overexpressing mice. PLoS ONE 7, e36397 (2012).

    CAS  PubMed Central  PubMed  Google Scholar 

  22. 22

    Nemani, V. M. et al. Increased expression of α-synuclein reduces neurotransmitter release by inhibiting synaptic vesicle reclustering after endocytosis. Neuron 65, 66–79 (2010).

    CAS  PubMed Central  PubMed  Google Scholar 

  23. 23

    Scott, D. & Roy, S. α-Synuclein inhibits intersynaptic vesicle mobility and maintains recycling-pool homeostasis. J. Neurosci. 32, 10129–10135 (2012).

    CAS  PubMed Central  PubMed  Google Scholar 

  24. 24

    Cooper, A. A. et al. α-Synuclein blocks ER–Golgi traffic and Rab1 rescues neuron loss in Parkinson's models. Science 313, 324–328 (2006).

    CAS  PubMed Central  PubMed  Google Scholar 

  25. 25

    Gitler, A. D. et al. The Parkinson's disease protein α-synuclein disrupts cellular Rab homeostasis. Proc. Natl Acad. Sci. USA 105, 145–150 (2008).

    CAS  Google Scholar 

  26. 26

    Chung, C. Y. et al. Identification and rescue of α-synuclein toxicity in Parkinson patient-derived neurons. Science 342, 983–987 (2013). This important paper shows how patient-derived neurons and yeast models of α-synucleinopathy can direct drug target discovery programmes.

    CAS  PubMed Central  PubMed  Google Scholar 

  27. 27

    Tardiff, D. F. et al. Yeast reveal a “druggable” Rsp5/Nedd4 network that ameliorates α-synuclein toxicity in neurons. Science 342, 979–983 (2013).

    CAS  PubMed Central  PubMed  Google Scholar 

  28. 28

    Tardiff, D. F., Khurana, V., Chung, C. Y. & Lindquist, S. From yeast to patient neurons and back again: powerful new discovery platform. Mov. Disord. 29, 1231–1240 (2014).

    CAS  PubMed  Google Scholar 

  29. 29

    Lee, V. M. & Trojanowski, J. Q. Mechanisms of Parkinson's disease linked to pathological α-synuclein: new targets for drug discovery. Neuron 52, 33–38 (2006).

    CAS  PubMed  Google Scholar 

  30. 30

    Maingay, M., Romero-Ramos, M., Carta, M. & Kirik, D. Ventral tegmental area dopamine neurons are resistant to human mutant α-synuclein overexpression. Neurobiol. Dis. 23, 522–532 (2006).

    CAS  PubMed  Google Scholar 

  31. 31

    Guzman, J. N., Sanchez-Padilla, J., Chan, C. S. & Surmeier, D. J. Robust pacemaking in substantia nigra dopaminergic neurons. J. Neurosci. 29, 11011–11019 (2009).

    CAS  PubMed Central  PubMed  Google Scholar 

  32. 32

    Matsuda, W. et al. Single nigrostriatal dopaminergic neurons form widely spread and highly dense axonal arborizations in the neostriatum. J. Neurosci. 29, 444–453 (2009). This elegant study shows the extent of the burden of SN dopamine neurons and, in doing so, contributes to our understanding of vulnerabilities of these neurons in PD.

    CAS  PubMed Central  PubMed  Google Scholar 

  33. 33

    Braak, H. & Del Tredici, K. Invited article: nervous system pathology in sporadic Parkinson disease. Neurology 70, 1916–1925 (2008).

    PubMed  Google Scholar 

  34. 34

    Fuchs, J. et al. Genetic variability in the SNCA gene influences α-synuclein levels in the blood and brain. FASEB J. 22, 1327–1334 (2008).

    CAS  PubMed  Google Scholar 

  35. 35

    Greenbaum, E. A. et al. The E46K mutation in α-synuclein increases amyloid fibril formation. J. Biol. Chem. 280, 7800–7807 (2005).

    CAS  PubMed  Google Scholar 

  36. 36

    Mata, I. F. et al. SNCA variant associated with Parkinson disease and plasma α-synuclein level. Arch. Neurol. 67, 1350–1356 (2010).

    PubMed Central  PubMed  Google Scholar 

  37. 37

    Hinault, M. P. et al. Stable α-synuclein oligomers strongly inhibit chaperone activity of the Hsp70 system by weak interactions with J-domain co-chaperones. J. Biol. Chem. 285, 38173–38182 (2010).

    CAS  PubMed Central  PubMed  Google Scholar 

  38. 38

    Xilouri, M., Brekk, O. R. & Stefanis, L. Autophagy and α-synuclein: relevance to Parkinson's disease and related synucleopathies. Mov. Disord. 31, 178–192 (2016).

    CAS  PubMed  Google Scholar 

  39. 39

    Dryanovski, D. I. et al. Calcium entry and α-synuclein inclusions elevate dendritic mitochondrial oxidant stress in dopaminergic neurons. J. Neurosci. 33, 10154–10164 (2013).

    CAS  PubMed Central  PubMed  Google Scholar 

  40. 40

    Guardia-Laguarta, C. et al. α-Synuclein is localized to mitochondria-associated ER membranes. J. Neurosci. 34, 249–259 (2014).

    CAS  PubMed Central  PubMed  Google Scholar 

  41. 41

    Mosharov, E. V. et al. Interplay between cytosolic dopamine, calcium, and α-synuclein causes selective death of substantia nigra neurons. Neuron 62, 218–229 (2009).

    CAS  PubMed Central  PubMed  Google Scholar 

  42. 42

    Volpicelli-Daley, L. A. Effects of α-synuclein on axonal transport. Neurobiol. Dis. http://dx.doi.org/10.1016/j.nbd.2016.12.008 (2016).

  43. 43

    Kim, C. et al. Antagonizing neuronal Toll-like receptor 2 prevents synucleinopathy by activating autophagy. Cell Rep. 13, 771–782 (2015).

    CAS  PubMed Central  PubMed  Google Scholar 

  44. 44

    Wang, S. et al. α-Synuclein, a chemoattractant, directs microglial migration via H2O2-dependent Lyn phosphorylation. Proc. Natl Acad. Sci. USA 112, E1926–E1935 (2015).

    CAS  PubMed  Google Scholar 

  45. 45

    Wong, Y. C. & Krainc, D. α-Synuclein toxicity in neurodegeneration: mechanism and therapeutic strategies. Nat. Med. 23, 1–13 (2017).

    CAS  PubMed  Google Scholar 

  46. 46

    Tofaris, G. K. et al. Pathological changes in dopaminergic nerve cells of the substantia nigra and olfactory bulb in mice transgenic for truncated human α-synuclein(1–120): implications for Lewy body disorders. J. Neurosci. 26, 3942–3950 (2006).

    CAS  PubMed Central  PubMed  Google Scholar 

  47. 47

    Wakamatsu, M. et al. Selective loss of nigral dopamine neurons induced by overexpression of truncated human α-synuclein in mice. Neurobiol. Aging 29, 574–585 (2008).

    CAS  PubMed  Google Scholar 

  48. 48

    Daher, J. P. et al. Conditional transgenic mice expressing C-terminally truncated human α-synuclein (αSyn119) exhibit reduced striatal dopamine without loss of nigrostriatal pathway dopaminergic neurons. Mol. Neurodegener. 4, 34 (2009).

    PubMed Central  PubMed  Google Scholar 

  49. 49

    Rieker, C. et al. Neuropathology in mice expressing mouse α-synuclein. PLoS ONE 6, e24834 (2011).

    CAS  PubMed Central  PubMed  Google Scholar 

  50. 50

    Chandra, S., Gallardo, G., Fernandez-Chacon, R., Schluter, O. M. & Sudhof, T. C. α-Synuclein cooperates with CSPα in preventing neurodegeneration. Cell 123, 383–396 (2005).

    CAS  PubMed  Google Scholar 

  51. 51

    Richfield, E. K. et al. Behavioral and neurochemical effects of wild-type and mutated human α-synuclein in transgenic mice. Exp. Neurol. 175, 35–48 (2002).

    CAS  PubMed  Google Scholar 

  52. 52

    Manning-Bog, A. B., McCormack, A. L., Purisai, M. G., Bolin, L. M. & Di Monte, D. A. α-Synuclein overexpression protects against paraquat-induced neurodegeneration. J. Neurosci. 23, 3095–3099 (2003).

    CAS  PubMed Central  PubMed  Google Scholar 

  53. 53

    Matsuoka, Y. et al. Lack of nigral pathology in transgenic mice expressing human α-synuclein driven by the tyrosine hydroxylase promoter. Neurobiol. Dis. 8, 535–539 (2001).

    CAS  PubMed  Google Scholar 

  54. 54

    Lin, X. et al. Leucine-rich repeat kinase 2 regulates the progression of neuropathology induced by Parkinson's-disease-related mutant α-synuclein. Neuron 64, 807–827 (2009).

    CAS  PubMed Central  PubMed  Google Scholar 

  55. 55

    Lim, Y., Kehm, V. M., Li, C., Trojanowski, J. Q. & Lee, V. M. Forebrain overexpression of α-synuclein leads to early postnatal hippocampal neuron loss and synaptic disruption. Exp. Neurol. 221, 86–97 (2010).

    CAS  PubMed  Google Scholar 

  56. 56

    Lin, X. et al. 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 (2012).

    CAS  PubMed Central  PubMed  Google Scholar 

  57. 57

    Nuber, S. et al. Neurodegeneration and motor dysfunction in a conditional model of Parkinson's disease. J. Neurosci. 28, 2471–2484 (2008).

    CAS  PubMed Central  PubMed  Google Scholar 

  58. 58

    Nuber, S. et al. Olfactory neuron-specific expression of A30P α-synuclein exacerbates dopamine deficiency and hyperactivity in a novel conditional model of early Parkinson's disease stages. Neurobiol. Dis. 44, 192–204 (2011).

    CAS  PubMed  Google Scholar 

  59. 59

    Kuo, Y. M. et al. Extensive enteric nervous system abnormalities in mice transgenic for artificial chromosomes containing Parkinson disease-associated α-synuclein gene mutations precede central nervous system changes. Hum. Mol. Genet. 19, 1633–1650 (2010).

    CAS  PubMed Central  PubMed  Google Scholar 

  60. 60

    Janezic, S. et al. Deficits in dopaminergic transmission precede neuron loss and dysfunction in a new Parkinson model. Proc. Natl Acad. Sci. USA 110, E4016–E4025 (2013). This key paper describes early events leading up to neurodegeneration, enhancing our understanding of physiological responses to α-syn overexpression.

    CAS  PubMed  Google Scholar 

  61. 61

    Petit, G. H. et al. Rasagiline ameliorates olfactory deficits in an α-synuclein mouse model of Parkinson's disease. PLoS ONE 8, e60691 (2013).

    CAS  PubMed Central  PubMed  Google Scholar 

  62. 62

    Rasmussen, N. B. et al. 5-HT2A receptor binding in the frontal cortex of Parkinson's disease patients and α-synuclein overexpressing mice: a postmortem study. Parkinsons Dis. 2016, 3682936 (2016).

    PubMed Central  PubMed  Google Scholar 

  63. 63

    Westerlund, M. et al. Lrrk2 and α-synuclein are co-regulated in rodent striatum. Mol. Cell. Neurosci. 39, 586–591 (2008).

    CAS  PubMed  Google Scholar 

  64. 64

    Gispert, S. et al. Transgenic mice expressing mutant A53T human α-synuclein show neuronal dysfunction in the absence of aggregate formation. Mol. Cell. Neurosci. 24, 419–429 (2003).

    CAS  PubMed  Google Scholar 

  65. 65

    Yavich, L. et al. Locomotor activity and evoked dopamine release are reduced in mice overexpressing A30P-mutated human α-synuclein. Neurobiol. Dis. 20, 303–313 (2005).

    CAS  PubMed  Google Scholar 

  66. 66

    Fleming, S. M. et al. Olfactory deficits in mice overexpressing human wildtype α-synuclein. Eur. J. Neurosci. 28, 247–256 (2008).

    PubMed Central  PubMed  Google Scholar 

  67. 67

    Giasson, B. I. et al. Neuronal α-synucleinopathy with severe movement disorder in mice expressing A53T human α-synuclein. Neuron 34, 521–533 (2002).

    CAS  PubMed  Google Scholar 

  68. 68

    Hallett, P. J., McLean, J. R., Kartunen, A., Langston, J. W. & Isacson, O. α-Synuclein overexpressing transgenic mice show internal organ pathology and autonomic deficits. Neurobiol. Dis. 47, 258–267 (2012).

    CAS  PubMed Central  PubMed  Google Scholar 

  69. 69

    Kahle, P. J. et al. Selective insolubility of α-synuclein in human Lewy body diseases is recapitulated in a transgenic mouse model. Am. J. Pathol. 159, 2215–2225 (2001).

    CAS  PubMed Central  PubMed  Google Scholar 

  70. 70

    Lee, H. J. et al. Transmission of synucleinopathies in the enteric nervous system of A53T α-synuclein transgenic mice. Exp. Neurobiol. 20, 181–188 (2011).

    PubMed Central  PubMed  Google Scholar 

  71. 71

    Neumann, M. et al. Misfolded proteinase K-resistant hyperphosphorylated α-synuclein in aged transgenic mice with locomotor deterioration and in human α-synucleinopathies. J. Clin. Invest. 110, 1429–1439 (2002).

    CAS  PubMed Central  PubMed  Google Scholar 

  72. 72

    Emmer, K. L., Waxman, E. A., Covy, J. P. & Giasson, B. I. E46K human α-synuclein transgenic mice develop Lewy-like and tau pathology associated with age-dependent, detrimental motor impairment. J. Biol. Chem. 286, 35104–35118 (2011).

    CAS  PubMed Central  PubMed  Google Scholar 

  73. 73

    Lee, M. K. et al. Human α-synuclein-harboring familial Parkinson's disease-linked Ala-53 → Thr mutation causes neurodegenerative disease with α-synuclein aggregation in transgenic mice. Proc. Natl Acad. Sci. USA 99, 8968–8973 (2002).

    CAS  PubMed  Google Scholar 

  74. 74

    Cabin, D. E. et al. Exacerbated synucleinopathy in mice expressing A53T SNCA on a Snca null background. Neurobiol. Aging 26, 25–35 (2005).

    CAS  PubMed  Google Scholar 

  75. 75

    Braak, H., Sastre, M., Bohl, J. R., de Vos, R. A. & Del Tredici, K. Parkinson's disease: lesions in dorsal horn layer I, involvement of parasympathetic and sympathetic pre- and postganglionic neurons. Acta Neuropathol. 113, 421–429 (2007).

    Google Scholar 

  76. 76

    Beach, T. G. et al. Multi-organ distribution of phosphorylated α-synuclein histopathology in subjects with Lewy body disorders. Acta Neuropathol. 119, 689–702 (2010).

    CAS  PubMed Central  PubMed  Google Scholar 

  77. 77

    Braak, H. et al. Staging of the intracerebral inclusion body pathology associated with idiopathic Parkinson's disease (preclinical and clinical stages). J. Neurol. 249 (Suppl. 3), iii1–iii5 (2002).

    Google Scholar 

  78. 78

    Braak, H., Ghebremedhin, E., Rub, U., Bratzke, H. & Del Tredici, K. Stages in the development of Parkinson's disease-related pathology. Cell Tissue Res. 318, 121–134 (2004).

    PubMed  Google Scholar 

  79. 79

    Farrell, K. F. et al. Non-motor parkinsonian pathology in aging A53T α-synuclein mice is associated with progressive synucleinopathy and altered enzymatic function. J. Neurochem. 128, 536–546 (2014).

    CAS  PubMed  Google Scholar 

  80. 80

    Noorian, A. R. et al. α-Synuclein transgenic mice display age-related slowing of gastrointestinal motility associated with transgene expression in the vagal system. Neurobiol. Dis. 48, 9–19 (2012). This important article demonstrates the link between α-syn expression in the vagal system and gastrointestinal motility.

    CAS  Google Scholar 

  81. 81

    Wang, L. et al. Mice overexpressing wild-type human α-synuclein display alterations in colonic myenteric ganglia and defecation. Neurogastroenterol. Motil. 24, e425–e436 (2012).

    CAS  PubMed Central  PubMed  Google Scholar 

  82. 82

    Bencsik, A., Muselli, L., Leboidre, M., Lakhdar, L. & Baron, T. Early and persistent expression of phosphorylated α-synuclein in the enteric nervous system of A53T mutant human α-synuclein transgenic mice. J. Neuropathol. Exp. Neurol. 73, 1144–1151 (2014).

    CAS  PubMed  Google Scholar 

  83. 83

    Price, D. L. et al. Longitudinal live imaging of retinal α-synuclein::GFP deposits in a transgenic mouse model of Parkinson's disease/dementia with Lewy bodies. Sci. Rep. 6, 29523 (2016).

    CAS  PubMed Central  PubMed  Google Scholar 

  84. 84

    Gray, M. T., Munoz, D. G., Gray, D. A., Schlossmacher, M. G. & Woulfe, J. M. α-Synuclein in the appendiceal mucosa of neurologically intact subjects. Mov. Disord. 29, 991–998 (2014).

    CAS  PubMed  Google Scholar 

  85. 85

    Visanji, N. P. et al. Colonic mucosal α-synuclein lacks specificity as a biomarker for Parkinson disease. Neurology 84, 609–616 (2015).

    CAS  PubMed Central  PubMed  Google Scholar 

  86. 86

    Antunes, L. et al. Similar α-synuclein staining in the colon mucosa in patients with Parkinson's disease and controls. Mov. Disord. 31, 1567–1570 (2016).

    CAS  PubMed  Google Scholar 

  87. 87

    Koob, A. O. et al. Lovastatin ameliorates α-synuclein accumulation and oxidation in transgenic mouse models of α-synucleinopathies. Exp. Neurol. 221, 267–274 (2010).

    CAS  PubMed  Google Scholar 

  88. 88

    Shaltiel-Karyo, R. et al. A blood–brain barrier (BBB) disrupter is also a potent α-synuclein (α-syn) aggregation inhibitor: a novel dual mechanism of mannitol for the treatment of Parkinson disease (PD). J. Biol. Chem. 288, 17579–17588 (2013).

    CAS  PubMed Central  PubMed  Google Scholar 

  89. 89

    Price, D. L. et al. Alterations in mGluR5 expression and signaling in Lewy body disease and in transgenic models of α-synucleinopathy — implications for excitotoxicity. PLoS ONE 5, e14020 (2010).

    PubMed Central  PubMed  Google Scholar 

  90. 90

    Martin, L. J. et al. Parkinson's disease α-synuclein transgenic mice develop neuronal mitochondrial degeneration and cell death. J. Neurosci. 26, 41–50 (2006).

    CAS  PubMed Central  PubMed  Google Scholar 

  91. 91

    Finkelstein, D. I. et al. Clioquinol improves cognitive, motor function, and microanatomy of the α-synuclein hA53T transgenic mice. ACS Chem. Neurosci. 7, 119–129 (2016).

    CAS  PubMed  Google Scholar 

  92. 92

    Kachroo, A. & Schwarzschild, M. A. Adenosine A2A receptor gene disruption protects in an α-synuclein model of Parkinson's disease. Ann. Neurol. 71, 278–282 (2012).

    CAS  PubMed Central  PubMed  Google Scholar 

  93. 93

    Kurz, A. et al. A53T-α-synuclein overexpression impairs dopamine signaling and striatal synaptic plasticity in old mice. PLoS ONE 5, e11464 (2010).

    PubMed Central  PubMed  Google Scholar 

  94. 94

    Clark, J. et al. Oral N-acetyl-cysteine attenuates loss of dopaminergic terminals in α-synuclein overexpressing mice. PLoS ONE 5, e12333 (2010).

    PubMed Central  PubMed  Google Scholar 

  95. 95

    Hansen, C. et al. A novel α-synuclein–GFP mouse model displays progressive motor impairment, olfactory dysfunction and accumulation of α-synuclein–GFP. Neurobiol. Dis. 56, 145–155 (2013).

    CAS  Google Scholar 

  96. 96

    Gomez-Isla, T. et al. Motor dysfunction and gliosis with preserved dopaminergic markers in human α-synuclein A30P transgenic mice. Neurobiol. Aging 24, 245–258 (2003).

    CAS  PubMed  Google Scholar 

  97. 97

    Freichel, C. et al. Age-dependent cognitive decline and amygdala pathology in α-synuclein transgenic mice. Neurobiol. Aging 28, 1421–1435 (2007).

    CAS  PubMed  Google Scholar 

  98. 98

    Rothman, S. M. et al. Neuronal expression of familial Parkinson's disease A53T α-synuclein causes early motor impairment, reduced anxiety and potential sleep disturbances in mice. J. Parkinsons Dis. 3, 215–229 (2013).

    CAS  PubMed  Google Scholar 

  99. 99

    Wakamatsu, M., Iwata, S., Funakoshi, T. & Yoshimoto, M. Dopamine receptor agonists reverse behavioral abnormalities of α-synuclein transgenic mouse, a new model of Parkinson's disease. J. Neurosci. Res. 86, 640–646 (2008).

    CAS  PubMed  Google Scholar 

  100. 100

    Kalia, L. V., Kalia, S. K. & Lang, A. E. Disease-modifying strategies for Parkinson's disease. Mov. Disord. 30, 1442–1450 (2015).

    CAS  PubMed  Google Scholar 

  101. 101

    Paumier, K. L. et al. Behavioral characterization of A53T mice reveals early and late stage deficits related to Parkinson's disease. PLoS ONE 8, e70274 (2013).

    CAS  PubMed Central  PubMed  Google Scholar 

  102. 102

    Games, D. et al. Reducing C-terminal-truncated α-synuclein by immunotherapy attenuates neurodegeneration and propagation in Parkinson's disease-like models. J. Neurosci. 34, 9441–9454 (2014).

    PubMed Central  PubMed  Google Scholar 

  103. 103

    George, S. et al. α-Synuclein transgenic mice exhibit reduced anxiety-like behaviour. Exp. Neurol. 210, 788–792 (2008).

    CAS  PubMed  Google Scholar 

  104. 104

    Graham, D. R. & Sidhu, A. Mice expressing the A53T mutant form of human α-synuclein exhibit hyperactivity and reduced anxiety-like behavior. J. Neurosci. Res. 88, 1777–1783 (2010).

    CAS  PubMed Central  PubMed  Google Scholar 

  105. 105

    Yamakado, H. et al. α-Synuclein BAC transgenic mice as a model for Parkinson's disease manifested decreased anxiety-like behavior and hyperlocomotion. Neurosci. Res. 73, 173–177 (2012).

    CAS  PubMed  Google Scholar 

  106. 106

    Kudo, T., Loh, D. H., Truong, D., Wu, Y. & Colwell, C. S. Circadian dysfunction in a mouse model of Parkinson's disease. Exp. Neurol. 232, 66–75 (2011).

    PubMed  Google Scholar 

  107. 107

    Zhang, S., Xiao, Q. & Le, W. Olfactory dysfunction and neurotransmitter disturbance in olfactory bulb of transgenic mice expressing human A53T mutant α-synuclein. PLoS ONE 10, e0119928 (2015).

    PubMed Central  PubMed  Google Scholar 

  108. 108

    Wang, L., Fleming, S. M., Chesselet, M. F. & Tache, Y. Abnormal colonic motility in mice overexpressing human wild-type α-synuclein. Neuroreport 19, 873–876 (2008).

    CAS  PubMed Central  PubMed  Google Scholar 

  109. 109

    Rockenstein, E. et al. 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 (2002).

    CAS  PubMed  Google Scholar 

  110. 110

    Hebron, M. L., Lonskaya, I. & Moussa, C. E. Nilotinib reverses loss of dopamine neurons and improves motor behavior via autophagic degradation of α-synuclein in Parkinson's disease models. Hum. Mol. Genet. 22, 3315–3328 (2013).

    CAS  PubMed Central  PubMed  Google Scholar 

  111. 111

    Kohl, Z. et al. Fluoxetine rescues impaired hippocampal neurogenesis in a transgenic A53T synuclein mouse model. Eur. J. Neurosci. 35, 10–19 (2012).

    PubMed Central  PubMed  Google Scholar 

  112. 112

    Mandler, M. et al. Next-generation active immunization approach for synucleinopathies: implications for Parkinson's disease clinical trials. Acta Neuropathol. 127, 861–879 (2014).

    CAS  PubMed Central  PubMed  Google Scholar 

  113. 113

    Masliah, E. et al. Effects of α-synuclein immunization in a mouse model of Parkinson's disease. Neuron 46, 857–868 (2005).

    CAS  PubMed  Google Scholar 

  114. 114

    Masliah, E. et al. Passive immunization reduces behavioral and neuropathological deficits in an α-synuclein transgenic model of Lewy body disease. PLoS ONE 6, e19338 (2011). This is a preclinical study using a transgenic mouse model showing that administration of antibodies to α-syn ameliorates behavioural deficits and pathology.

    CAS  PubMed Central  PubMed  Google Scholar 

  115. 115

    Lindstrom, V. et al. Immunotherapy targeting α-synuclein protofibrils reduced pathology in (Thy-1)-h[A30P] α-synuclein mice. Neurobiol. Dis. 69, 134–143 (2014).

    PubMed  Google Scholar 

  116. 116

    Roy, A., Rangasamy, S. B., Kundu, M. & Pahan, K. BPOZ-2 gene delivery ameliorates α-synucleinopathy in A53T transgenic mouse model of Parkinson's disease. Sci. Rep. 6, 22067 (2016).

    CAS  PubMed Central  PubMed  Google Scholar 

  117. 117

    Rocha, E. M. et al. Glucocerebrosidase gene therapy prevents α-synucleinopathy of midbrain dopamine neurons. Neurobiol. Dis. 82, 495–503 (2015).

    CAS  PubMed  Google Scholar 

  118. 118

    Niu, Y. et al. Early Parkinson's disease symptoms in α-synuclein transgenic monkeys. Hum. Mol. Genet. 24, 2308–2317 (2015).

    CAS  PubMed  Google Scholar 

  119. 119

    Baekelandt, V. et al. Characterization of lentiviral vector-mediated gene transfer in adult mouse brain. Hum. Gene Ther. 13, 841–853 (2002).

    CAS  PubMed  Google Scholar 

  120. 120

    Kirik, D. et al. Parkinson-like neurodegeneration induced by targeted overexpression of α-synuclein in the nigrostriatal system. J. Neurosci. 22, 2780–2791 (2002).

    CAS  PubMed Central  PubMed  Google Scholar 

  121. 121

    Lo Bianco, C., Ridet, J.-L., Schneider, B. L., Deglon, N. & Aebischer, P. α-Synucleinopathy and selective dopaminergic neuron loss in a rat lentiviral-based model of Parkinson's disease. Proc. Natl Acad. Sci. USA 99, 10813–10818 (2002).

    CAS  PubMed  Google Scholar 

  122. 122

    Lo Bianco, C. et al. Lentiviral vector delivery of parkin prevents dopaminergic degeneration in an α-synuclein rat model of Parkinson's disease. Proc. Natl Acad. Sci. USA 101, 17510–17515 (2004).

    CAS  Google Scholar 

  123. 123

    Klein, R. L., King, M. A., Hamby, M. E. & Meyer, E. M. Dopaminergic cell loss induced by human A30P α-synuclein gene transfer to the rat substantia nigra. Hum. Gene Ther. 13, 605–612 (2002).

    CAS  Google Scholar 

  124. 124

    St Martin, J. L. et al. Dopaminergic neuron loss and up-regulation of chaperone protein mRNA induced by targeted over-expression of α-synuclein in mouse substantia nigra. J. Neurochem. 100, 1449–1457 (2007).

    CAS  PubMed  Google Scholar 

  125. 125

    Theodore, S., Cao, S., McLean, P. J. & Standaert, D. G. Targeted overexpression of human α-synuclein triggers microglial activation and an adaptive immune response in a mouse model of Parkinson disease. J. Neuropathol. Exp. Neurol. 67, 1149–1158 (2008).

    CAS  PubMed Central  PubMed  Google Scholar 

  126. 126

    Decressac, M., Mattsson, B., Lundblad, M., Weikop, P. & Bjorklund, A. Progressive neurodegenerative and behavioural changes induced by AAV-mediated overexpression of α-synuclein in midbrain dopamine neurons. Neurobiol. Dis. 45, 939–953 (2012).

    CAS  PubMed  Google Scholar 

  127. 127

    Van der Perren, A. et al. Longitudinal follow-up and characterization of a robust rat model for Parkinson's disease based on overexpression of α-synuclein with adeno-associated viral vectors. Neurobiol. Aging 36, 1543–1558 (2015).

    CAS  Google Scholar 

  128. 128

    Kordower, J. H. et al. Disease duration and the integrity of the nigrostriatal system in Parkinson's disease. Brain 136, 2419–2431 (2013). This is a well-controlled study providing evidence of the degree of dopaminergic anatomy that remains at varying stages of PD — important for consideration of early-start clinical trials.

    PubMed Central  PubMed  Google Scholar 

  129. 129

    Fearnley, J. M. & Lees, A. J. Ageing and Parkinson's disease: substantia nigra regional selectivity. Brain 114, 2283–2301 (1991).

    PubMed  Google Scholar 

  130. 130

    Greffard, S. et al. Motor score of the Unified Parkinson Disease Rating Scale as a good predictor of Lewy body-associated neuronal loss in the substantia nigra. Arch. Neurol. 63, 584–588 (2006).

    PubMed  Google Scholar 

  131. 131

    Ma, S. Y., Roytta, M., Rinne, J. O., Collan, Y. & Rinne, U. K. Correlation between neuromorphometry in the substantia nigra and clinical features in Parkinson's disease using disector counts. J. Neurol. Sci. 151, 83–87 (1997).

    CAS  PubMed  Google Scholar 

  132. 132

    Cheng, H. C., Ulane, C. M. & Burke, R. E. Clinical progression in Parkinson disease and the neurobiology of axons. Ann. Neurol. 67, 715–725 (2010).

    PubMed Central  PubMed  Google Scholar 

  133. 133

    Kirik, D., Rosenblad, C. & Bjorklund, A. 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, 259–277 (1998).

    CAS  PubMed  Google Scholar 

  134. 134

    Mayo, J. C. et al. Melatonin and Parkinson's disease. Endocrine 27, 169–178 (2005).

    CAS  PubMed  Google Scholar 

  135. 135

    Koprich, J., Johnston, T., Reyes, M., Sun, X. & Brotchie, J. Expression of human A53T α-synuclein in the rat substantia nigra using a novel AAV1/2 vector produces a rapidly evolving pathology with protein aggregation, dystrophic neurite architecture and nigrostriatal degeneration with potential to model the pathology of Parkinson's disease. Mol. Neurodegener. 5, 43 (2010).

    PubMed Central  PubMed  Google Scholar 

  136. 136

    Koprich, J. B. et al. Progressive neurodegeneration or endogenous compensation in an animal model of Parkinson's disease produced by decreasing doses of α-synuclein. PLoS ONE 6, e17698 (2011).

    CAS  PubMed Central  PubMed  Google Scholar 

  137. 137

    Azeredo da Silveira, S. et al. Phosphorylation does not prompt, nor prevent, the formation of α-synuclein toxic species in a rat model of Parkinson's disease. Hum. Mol. Genet. 18, 872–887 (2009).

    CAS  PubMed  Google Scholar 

  138. 138

    Oliveras-Salva, M. et al. rAAV2/7 vector-mediated overexpression of α-synuclein in mouse substantia nigra induces protein aggregation and progressive dose-dependent neurodegeneration. Mol. Neurodegener. 8, 44 (2013).

    PubMed Central  PubMed  Google Scholar 

  139. 139

    Yamada, M., Iwatsubo, T., Mizuno, Y. & Mochizuki, H. Overexpression of α-synuclein in rat substantia nigra results in loss of dopaminergic neurons, phosphorylation of α-synuclein and activation of caspase-9: resemblance to pathogenetic changes in Parkinson's disease. J. Neurochem. 91, 451–461 (2004).

    CAS  PubMed  Google Scholar 

  140. 140

    Lauwers, E. et al. Non-invasive imaging of neuropathology in a rat model of α-synuclein overexpression. Neurobiol. Aging 28, 248–257 (2007).

    CAS  PubMed  Google Scholar 

  141. 141

    McFarland, N. R., Lee, J. S., Hyman, B. T. & McLean, P. J. Comparison of transduction efficiency of recombinant AAV serotypes 1, 2, 5, and 8 in the rat nigrostriatal system. J. Neurochem. 109, 838–845 (2009).

    CAS  PubMed Central  PubMed  Google Scholar 

  142. 142

    Chung, C. Y., Koprich, J. B., Siddiqi, H. & Isacson, O. Dynamic changes in presynaptic and axonal transport proteins combined with striatal neuroinflammation precede dopaminergic neuronal loss in a rat model of AAV α-synucleinopathy. J. Neurosci. 29, 3365–3373 (2009).

    CAS  PubMed Central  PubMed  Google Scholar 

  143. 143

    Chu, Y. et al. Alterations in axonal transport motor proteins in sporadic and experimental Parkinson's disease. Brain 135, 2058–2073 (2012).

    PubMed Central  PubMed  Google Scholar 

  144. 144

    He, Q. et al. Treatment with trehalose prevents behavioral and neurochemical deficits produced in an AAV α-synuclein rat model of Parkinson's disease. Mol. Neurobiol. 53, 2258–2268 (2016).

    CAS  PubMed  Google Scholar 

  145. 145

    Qin, H. et al. Inhibition of the JAK/STAT pathway protects against α-synuclein-induced neuroinflammation and dopaminergic neurodegeneration. J. Neurosci. 36, 5144–5159 (2016).

    CAS  PubMed Central  PubMed  Google Scholar 

  146. 146

    Van der Perren, A. et al. FK506 reduces neuroinflammation and dopaminergic neurodegeneration in an α-synuclein-based rat model for Parkinson's disease. Neurobiol. Aging 36, 1559–1568 (2015).

    CAS  PubMed  Google Scholar 

  147. 147

    Shahaduzzaman, M. et al. Anti-human α-synuclein N-terminal peptide antibody protects against dopaminergic cell death and ameliorates behavioral deficits in an AAV-α-synuclein rat model of Parkinson's disease. PLoS ONE 10, e0116841 (2015).

    PubMed Central  PubMed  Google Scholar 

  148. 148

    Aldrin-Kirk, P., Davidsson, M., Holmqvist, S., Li, J. Y. & Bjorklund, T. Novel AAV-based rat model of forebrain synucleinopathy shows extensive pathologies and progressive loss of cholinergic interneurons. PLoS ONE 9, e100869 (2014).

    PubMed Central  PubMed  Google Scholar 

  149. 149

    Ulusoy, A. et al. Caudo-rostral brain spreading of α-synuclein through vagal connections. EMBO Mol. Med. 5, 1119–1127 (2013).

    PubMed  Google Scholar 

  150. 150

    Vermilyea, S. C. & Emborg, M. E. α-Synuclein and nonhuman primate models of Parkinson's disease. J. Neurosci. Methods 255, 38–51 (2015).

    CAS  PubMed Central  PubMed  Google Scholar 

  151. 151

    Eslamboli, A. et al. Long-term consequences of human α-synuclein overexpression in the primate ventral midbrain. Brain 130, 799–815 (2007). This is a follow-up study to an earlier proof-of-concept report further characterizing the effects of AAV delivery of α-syn to the primate brain.

    PubMed  Google Scholar 

  152. 152

    Kirik, D. et al. Nigrostriatal α-synucleinopathy induced by viral vector-mediated overexpression of human α-synuclein: a new primate model of Parkinson's disease. Proc. Natl Acad. Sci. USA 100, 2884–2889 (2003).

    CAS  PubMed  Google Scholar 

  153. 153

    Yang, W. et al. Mutant α-synuclein causes age-dependent neuropathology in monkey brain. J. Neurosci. 35, 8345–8358 (2015).

    CAS  PubMed Central  PubMed  Google Scholar 

  154. 154

    Koprich, J. B., Johnston, T. H., Reyes, G., Omana, V. & Brotchie, J. M. Towards a non-human primate model of α-synucleinopathy for development of therapeutics for Parkinson's disease: optimization of AAV1/2 delivery parameters to drive sustained expression of alpha synuclein and dopaminergic degeneration in macaque. PLoS ONE 30, e0167235 (2016).

    Google Scholar 

  155. 155

    Rey, N. L. et al. Widespread transneuronal propagation of α-synucleinopathy triggered in olfactory bulb mimics prodromal Parkinson's disease. J. Exp. Med. 213, 1759–1778 (2016).

    CAS  PubMed Central  PubMed  Google Scholar 

  156. 156

    Holmqvist, S. et al. Direct evidence of Parkinson pathology spread from the gastrointestinal tract to the brain in rats. Acta Neuropathol. 128, 805–820 (2014).

    PubMed  Google Scholar 

  157. 157

    Desplats, P. et al. Inclusion formation and neuronal cell death through neuron-to-neuron transmission of α-synuclein. Proc. Natl Acad. Sci. USA 106, 13010–13015 (2009).

    CAS  Google Scholar 

  158. 158

    Hansen, C. et al. α-Synuclein propagates from mouse brain to grafted dopaminergic neurons and seeds aggregation in cultured human cells. J. Clin. Invest. 121, 715–725 (2011).

    CAS  PubMed Central  PubMed  Google Scholar 

  159. 159

    Volpicelli-Daley, L. A. et al. Exogenous α-synuclein fibrils induce Lewy body pathology leading to synaptic dysfunction and neuron death. Neuron 72, 57–71 (2011).

    CAS  PubMed Central  PubMed  Google Scholar 

  160. 160

    Kordower, J. H. et al. Transfer of host-derived α synuclein to grafted dopaminergic neurons in rat. Neurobiol. Dis. 43, 552–557 (2011).

    CAS  PubMed Central  PubMed  Google Scholar 

  161. 161

    Reyes, J. F. et al. α-Synuclein transfers from neurons to oligodendrocytes. Glia 62, 387–398 (2014).

    PubMed  Google Scholar 

  162. 162

    Luk, K. C. et al. Pathological α-synuclein transmission initiates Parkinson-like neurodegeneration in nontransgenic mice. Science 338, 949–953 (2012). This study highlights how spreading of α-syn can occur in the normal mammalian brain, with implications for mechanisms of multisystem involvement in human PD.

    CAS  PubMed Central  PubMed  Google Scholar 

  163. 163

    Mougenot, A. L. et al. Transmission of prion strains in a transgenic mouse model overexpressing human A53T mutated α-synuclein. J. Neuropathol. Exp. Neurol. 70, 377–385 (2011).

    CAS  PubMed  Google Scholar 

  164. 164

    Luk, K. C. et al. Intracerebral inoculation of pathological α-synuclein initiates a rapidly progressive neurodegenerative α-synucleinopathy in mice. J. Exp. Med. 209, 975–986 (2012).

    CAS  PubMed Central  PubMed  Google Scholar 

  165. 165

    Masuda-Suzukake, M. et al. Prion-like spreading of pathological α-synuclein in brain. Brain 136, 1128–1138 (2013).

    PubMed Central  PubMed  Google Scholar 

  166. 166

    Paumier, K. L. et al. Intrastriatal injection of pre-formed mouse α-synuclein fibrils into rats triggers α-synuclein pathology and bilateral nigrostriatal degeneration. Neurobiol. Dis. 82, 185–199 (2015).

    CAS  PubMed Central  PubMed  Google Scholar 

  167. 167

    Tran, H. T. et al. α-Synuclein immunotherapy blocks uptake and templated propagation of misfolded α-synuclein and neurodegeneration. Cell Rep. 7, 2054–2065 (2014).

    CAS  PubMed Central  PubMed  Google Scholar 

  168. 168

    Recasens, A. et al. Lewy body extracts from Parkinson disease brains trigger α-synuclein pathology and neurodegeneration in mice and monkeys. Ann. Neurol. 75, 351–362 (2014).

    CAS  PubMed  Google Scholar 

  169. 169

    Kordower, J. H. et al. Intrastriatal alpha synuclein preformed fibrils in macaque monkeys: neuronal transport, longterm imaging and neuropathologic changes [abstract]. Society for Neuroscience Meeting 2014, Washington D.C. 409.07/I11 (2014).

  170. 170

    Shimozawa, A. et al. Propagation of pathological α-synuclein in marmoset brain. Acta Neuropathol. Commun. 5, 12 (2017).

    PubMed Central  PubMed  Google Scholar 

  171. 171

    Ip, C. W. et al. AAV1/2-induced overexpression of A53T-α-synuclein in the substantia nigra results in degeneration of the nigrostriatal system with Lewy-like pathology and motor impairment: a new mouse model for Parkinson's disease. Acta Neuropathol. Commun. 5, 11 (2017).

    PubMed Central  PubMed  Google Scholar 

  172. 172

    Marras, C. et al. Nomenclature of genetic movement disorders: recommendations of the International Parkinson and Movement Disorder Society task force. Mov. Disord. 31, 436–457 (2016).

    PubMed  Google Scholar 

  173. 173

    Moore, D. J., West, A. B., Dawson, V. L. & Dawson, T. M. Molecular pathophysiology of Parkinson's disease. Annu. Rev. Neurosci. 28, 57–87 (2005).

    CAS  PubMed  Google Scholar 

  174. 174

    Trojanowski, J. Q. & Lee, V. M. Aggregation of neurofilament and α-synuclein proteins in Lewy bodies: implications for the pathogenesis of Parkinson disease and Lewy body dementia. Arch. Neurol. 55, 151–152 (1998).

    CAS  PubMed  Google Scholar 

  175. 175

    Martin, I., Kim, J. W., Dawson, V. L. & Dawson, T. M. LRRK2 pathobiology in Parkinson's disease. J. Neurochem. 131, 554–565 (2014).

    CAS  PubMed Central  PubMed  Google Scholar 

  176. 176

    Nichols, R. J. et al. 14-3-3 binding to LRRK2 is disrupted by multiple Parkinson's disease-associated mutations and regulates cytoplasmic localization. Biochem. J. 430, 393–404 (2010).

    CAS  PubMed Central  PubMed  Google Scholar 

  177. 177

    Dodson, M. W. & Guo, M. Pink1, Parkin, DJ-1 and mitochondrial dysfunction in Parkinson's disease. Curr. Opin. Neurobiol. 17, 331–337 (2007).

    CAS  PubMed  Google Scholar 

  178. 178

    Whitworth, A. J. & Pallanck, L. J. The PINK1/Parkin pathway: a mitochondrial quality control system? J. Bioenerg. Biomembr. 41, 499–503 (2009).

    CAS  PubMed  Google Scholar 

  179. 179

    Dawson, T. M. & Dawson, V. L. The role of parkin in familial and sporadic Parkinson's disease. Mov. Disord. 25 (Suppl. 1), S32–S39 (2010).

    PubMed Central  PubMed  Google Scholar 

  180. 180

    Ko, H. S. et al. Phosphorylation by the c-Abl protein tyrosine kinase inhibits parkin's ubiquitination and protective function. Proc. Natl Acad. Sci. USA 107, 16691–16696 (2010).

    CAS  PubMed  Google Scholar 

  181. 181

    Shin, J. H. et al. PARIS (ZNF746) repression of PGC-1α contributes to neurodegeneration in Parkinson's disease. Cell 144, 689–702 (2011).

    CAS  PubMed Central  PubMed  Google Scholar 

  182. 182

    Bose, A. & Beal, M. F. Mitochondrial dysfunction in Parkinson's disease. J. Neurochem. 139, 216–231 (2016).

    CAS  PubMed  Google Scholar 

  183. 183

    Rousseaux, M. W. et al. Progressive dopaminergic cell loss with unilateral-to-bilateral progression in a genetic model of Parkinson disease. Proc. Natl Acad. Sci. USA 109, 15918–15923 (2012).

    CAS  PubMed  Google Scholar 

  184. 184

    Kalia, L. V. et al. Clinical correlations with Lewy body pathology in LRRK2-related Parkinson disease. JAMA Neurol. 72, 100–105 (2015).

    PubMed Central  PubMed  Google Scholar 

  185. 185

    Poulopoulos, M., Levy, O. A. & Alcalay, R. N. The neuropathology of genetic Parkinson's disease. Mov. Disord. 27, 831–842 (2012).

    CAS  PubMed Central  PubMed  Google Scholar 

  186. 186

    Taipa, R. et al. DJ-1 linked parkinsonism (PARK7) is associated with Lewy body pathology. Brain 139, 1680–1687 (2016).

    PubMed  Google Scholar 

  187. 187

    Polymeropoulos, M. H. et al. Mutation in the α-synuclein gene identified in families with Parkinson's disease. Science 276, 2045–2047 (1997).

    CAS  PubMed  Google Scholar 

  188. 188

    Kruger, R. et al. Ala30Pro mutation in the gene encoding α-synuclein in Parkinson's disease. Nat. Genet. 18, 106–108 (1998).

    CAS  Google Scholar 

  189. 189

    Zarranz, J. J. et al. The new mutation, E46K, of α-synuclein causes Parkinson and Lewy body dementia. Ann. Neurol. 55, 164–173 (2004).

    CAS  Google Scholar 

  190. 190

    Appel-Cresswell, S. et al. α-Synuclein p.H50Q, a novel pathogenic mutation for Parkinson's disease. Mov. Disord. 28, 811–813 (2013).

    CAS  PubMed  Google Scholar 

  191. 191

    Proukakis, C. et al. A novel α-synuclein missense mutation in Parkinson disease. Neurology 80, 1062–1064 (2013).

    PubMed Central  PubMed  Google Scholar 

  192. 192

    Lesage, S. et al. G51D α-synuclein mutation causes a novel parkinsonian-pyramidal syndrome. Ann. Neurol. 73, 459–471 (2013).

    CAS  Google Scholar 

  193. 193

    Martikainen, M. H., Paivarinta, M., Hietala, M. & Kaasinen, V. Clinical and imaging findings in Parkinson disease associated with the A53E SNCA mutation. Neurol. Genet. 1, e27 (2015).

    PubMed Central  PubMed  Google Scholar 

  194. 194

    Pasanen, P. et al. Novel α-synuclein mutation A53E associated with atypical multiple system atrophy and Parkinson's disease-type pathology. Neurobiol. Aging 35, 2180.e1–2180.e5 (2014).

    CAS  Google Scholar 

  195. 195

    Farrer, M. et al. Comparison of kindreds with parkinsonism and α-synuclein genomic multiplications. Ann. Neurol. 55, 174–179 (2004).

    CAS  PubMed  Google Scholar 

  196. 196

    Nishioka, K. et al. Clinical heterogeneity of α-synuclein gene duplication in Parkinson's disease. Ann. Neurol. 59, 298–309 (2006).

    CAS  PubMed  Google Scholar 

  197. 197

    Buell, A. K. et al. Solution conditions determine the relative importance of nucleation and growth processes in α-synuclein aggregation. Proc. Natl Acad. Sci. USA 111, 7671–7676 (2014).

    CAS  PubMed  Google Scholar 

  198. 198

    Galvagnion, C. et al. Lipid vesicles trigger α-synuclein aggregation by stimulating primary nucleation. Nat. Chem. Biol. 11, 229–234 (2015).

    CAS  PubMed Central  PubMed  Google Scholar 

  199. 199

    Ibanez, P. et al. Causal relation between α-synuclein gene duplication and familial Parkinson's disease. Lancet 364, 1169–1171 (2004).

    CAS  Google Scholar 

  200. 200

    Nalls, M. A. et al. Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson's disease. Nat. Genet. 46, 989–993 (2014).

    CAS  PubMed Central  PubMed  Google Scholar 

  201. 201

    Singleton, A. B. et al. α-Synuclein locus triplication causes Parkinson's disease. Science 302, 841 (2003).

    CAS  PubMed  Google Scholar 

  202. 202

    Walsh, D. M. & Selkoe, D. J. A critical appraisal of the pathogenic protein spread hypothesis of neurodegeneration. Nat. Rev. Neurosci. 17, 251–260 (2016).

    CAS  PubMed Central  PubMed  Google Scholar 

  203. 203

    Engelender, S. & Isacson, O. The threshold theory for Parkinson's disease. Trends Neurosci. 40, 4–14 (2017).

    CAS  PubMed  Google Scholar 

  204. 204

    Surmeier, D. J., Obeso, J. A. & Halliday, G. M. Selective neuronal vulnerability in Parkinson disease. Nat. Rev. Neurosci. 18, 101–113 (2017).

    CAS  PubMed Central  PubMed  Google Scholar 

  205. 205

    Fleming, S. M. et al. Early and progressive sensorimotor anomalies in mice overexpressing wild-type human α-synuclein. J. Neurosci. 24, 9434–9440 (2004).

    CAS  PubMed Central  PubMed  Google Scholar 

  206. 206

    Fleming, S. M. et al. A pilot trial of the microtubule-interacting peptide (NAP) in mice overexpressing alpha-synuclein shows improvement in motor function and reduction of α-synuclein inclusions. Mol. Cell. Neurosci. 46, 597–606 (2011).

    CAS  PubMed  Google Scholar 

  207. 207

    Kim, C. et al. Hypoestoxide reduces neuroinflammation and α-synuclein accumulation in a mouse model of Parkinson's disease. J. Neuroinflamm. 12, 236 (2015).

    Google Scholar 

  208. 208

    Kahle, P. J. et al. Subcellular localization of wild-type and Parkinson's disease-associated mutant α-synuclein in human and transgenic mouse brain. J. Neurosci. 20, 6365–6373 (2000).

    CAS  PubMed  Google Scholar 

  209. 209

    Masliah, E. et al. Dopaminergic loss and inclusion body formation in α-synuclein mice: implications for neurodegenerative disorders. Science 287, 1265–1269 (2000).

    CAS  PubMed  Google Scholar 

  210. 210

    Amschl, D. et al. Time course and progression of wild type α-synuclein accumulation in a transgenic mouse model. BMC Neurosci. 14, 6 (2013).

    CAS  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgements

L.V.K. holds a Canadian Institutes of Health Research (CIHR) Clinician-Scientist Award.

Author information

Affiliations

Authors

Corresponding author

Correspondence to James B. Koprich.

Ethics declarations

Competing interests

J.B.K. and J.M.B. have equity stakes in, and have received consultancy fees from, Atuka Inc., Toronto, Canada, a contract research organization that provides services using some of the animal models discussed in this Review.

PowerPoint slides

Glossary

Bradykinesia

Slowness of movement and decrement in amplitude or speed (or progressive hesitations or halts) as movements are continued.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine

(MPTP). A neurotoxin that, when injected into most animals, will produce a selective lesion of the dopamine system that can be used to model nigral degeneration.

Ganglioside

Sialic acid-containing glycosphingolipid differentiated by the structure of its carbohydrate chains. Gangliosides are primarily localized in plasma membranes and have prominent roles in various cell functions.

Protofibrils, fibrils and oligomers

Different α-synuclein conformers associated with the pathogenesis of Lewy body diseases, including Parkinson disease. Fibrils in particular are found in abundance in Lewy bodies.

Rapid eye movement (REM) sleep behaviour disorder

(RBD). A parasomnia characterized by abnormal or disruptive behaviours (such as shouting, gesturing or kicking) that occur during REM sleep and are often related to dream enactment.

Tetracycline-controlled transcriptional activation

Inducible gene expression in which transcription of a target transgene is reversibly turned on or off in the presence of tetracycline or a derivative (such as doxycycline).

pSer129

Phosphorylation site associated with toxic forms of α-synuclein.

'Core and halo' morphology

The classical morphology of a nigral Lewy body: a spherical cytoplasmic inclusion with a hyaline eosinophilic core and a narrow, pale-stained halo.

Morris water maze

A commonly used behavioural test for mouse or rat that assesses spatial learning and memory.

Construct validity

The ability of a model to measure what it is intended to measure.

Face validity

The ability of a model to reproduce the clinical and pathological features of the human disease.

Passive immunotherapies

Exogenous antibodies specific to an antigen (such as α-synuclein) that are delivered by intravenous, subcutaneous or intraperitoneal injection.

Active immunotherapies

Vaccinations that activate the immune system of the body to produce endogenous antibodies specific to an antigen (such as α-synuclein).

Hybrid serotype adeno-associated viruses

Adeno-associated viruses produced to express two viral serotypes on their particle surface.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Koprich, J., Kalia, L. & Brotchie, J. Animal models of α-synucleinopathy for Parkinson disease drug development. Nat Rev Neurosci 18, 515–529 (2017). https://doi.org/10.1038/nrn.2017.75

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing