1. McCann, H., Stevens, C. H., Cartwright, H. & Halliday, G. M. α-Synucleinopathy phenotypes. Parkinsonism Relat. Disord. 20, S62–S67 (2014).

2. Lees, A. J., Hardy, J. & Revesz, T. Parkinson’s disease. Lancet 373, 2055–2066 (2009).

3. Hawkes, C. H., Del Tredici, K. & Braak, H. A timeline for Parkinson’s disease. Parkinsonism Relat. Disord. 16, 79–84 (2010).

4. Sánchez-Ferro, Á. et al. In vivo gastric detection of α-synuclein inclusions in Parkinson’s disease. Mov. Disord. 30, 517–524 (2015).

5. Shannon, K. M. et al. Alpha-synuclein in colonic submucosa in early untreated Parkinson’s disease. Mov. Disord. 27, 709–715 (2012).

6. Yoo, B. B. & Mazmanian, S. K. The enteric network: interactions between the immune and nervous systems of the gut. Immunity 46, 910–926 (2017).

7. Braak, H., Rüb, U., Gai, W. P. & Del Tredici, K. Idiopathic Parkinson’s disease: possible routes by which vulnerable neuronal types may be subject to neuroinvasion by an unknown pathogen. J. Neural Transm. 110, 517–536 (2003).

8. 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).

9. Uemura, N. et al. Inoculation of α-synuclein preformed fibrils into the mouse gastrointestinal tract induces Lewy body-like aggregates in the brainstem via the vagus nerve. Mol. Neurodegener. 13, 21 (2018).

10. Kim, S. et al. Transneuronal propagation of pathologic α-synuclein from the gut to the brain models Parkinson’s disease. Neuron https://doi.org/10.1016/j.neuron.2019.05.035 (2019).

11. Devos, D. et al. Colonic inflammation in Parkinson’s disease. Neurobiol. Dis. 50, 42–48 (2013).

12. Codolo, G. et al. Triggering of inflammasome by aggregated α–synuclein, an inflammatory response in synucleinopathies. PLoS ONE 8, e55375 (2013).

13. Amor, S., Puentes, F., Baker, D. & Valk, P. V. D. Inflammation in neurodegenerative diseases. Immunology 129, 154–169 (2010).

14. Chu, Y., Dodiya, H., Aebischer, P., Olanow, C. W. & Kordower, J. H. Alterations in lysosomal and proteasomal markers in Parkinson’s disease: relationship to alpha-synuclein inclusions. Neurobiol. Dis. 35, 385–398 (2009).

15. Neumann, J. et al. Glucocerebrosidase mutations in clinical and pathologically proven Parkinson’s disease. Brain 132, 1783–1794 (2009).

16. Fishbein, I., Kuo, Y.-M., Giasson, B. I. & Nussbaum, R. L. Augmentation of phenotype in a transgenic Parkinson mouse heterozygous for a gaucher mutation. Brain 137, 3235–3247 (2014).

17. Mazzulli, J. R. et al. Gaucher disease glucocerebrosidase and α-synuclein form a bidirectional pathogenic loop in synucleinopathies. Cell 146, 37–52 (2011).

18. Sardi, S. P. et al. CNS expression of glucocerebrosidase corrects α-synuclein pathology and memory in a mouse model of Gaucher-related synucleinopathy. Proc. Natl Acad. Sci. USA 108, 12101–12106 (2011).

19. O’Sullivan, S. S. et al. Nonmotor symptoms as presenting complaints in Parkinson’s disease: a clinicopathological study. Mov. Disord. 23, 101–106 (2008).

20. Volpicelli-Daley, L. A., Luk, K. C. & Lee, V. M.-Y. Addition of exogenous α-synuclein preformed fibrils to primary neuronal cultures to seed recruitment of endogenous α-synuclein to Lewy body and Lewy neurite-like aggregates. Nat. Protoc. 9, 2135–2146 (2014).

21. Luk, K. C. et al. Pathological α-synuclein transmission initiates Parkinson-like neurodegeneration in nontransgenic mice. Science 338, 949–953 (2012).

22. 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).

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

24. Chesselet, M.-F. et al. A progressive mouse model of Parkinson’s disease: the Thy1-aSyn (“Line 61”) mice. Neurotherapeutics 9, 297–314 (2012).

25. Schafer, K.-H., Mestres, P., Marz, P. & Rose-John, S. The IL-6/sIL-6R fusion protein hyper-IL-6 promotes neurite outgrowth and neuron survival in cultured enteric neurons. J. Interferon Cytokine Res. 19, 527–532 (1999).

26. De Schepper, S. et al. Self-maintaining gut macrophages are essential for intestinal homeostasis. Cell 175, 400–415.e13 (2018).

27. Sehgal, A. et al. The role of CSF1R-dependent macrophages in control of the intestinal stem-cell niche. Nat. Commun. 9, 1272 (2018).

28. Barrenschee, M. et al. Distinct pattern of enteric phospho-alpha-synuclein aggregates and gene expression profiles in patients with Parkinson’s disease. Acta Neuropathol. Commun. 5, 1 (2017).

29. Fujiwara, H. et al. α-Synuclein is phosphorylated in synucleinopathy lesions. Nat. Cell Biol. 4, 160–164 (2002).

30. Grassi, D. et al. Identification of a highly neurotoxic α-synuclein species inducing mitochondrial damage and mitophagy in Parkinson’s disease. Proc. Natl Acad. Sci. USA 115, E2634–E2643 (2018).

31. Sampson, T. R. et al. Gut microbiota regulate motor deficits and neuroinflammation in a model of Parkinson’s disease. Cell 167, 1469–1480.e12 (2016).

32. Morabito, G. et al. AAV-PHP.B-mediated global-scale expression in the mouse nervous system enables GBA1 gene therapy for wide protection from synucleinopathy. Mol. Ther. https://doi.org/10.1016/j.ymthe.2017.08.004 (2017).

33. Chan, K. Y. et al. Engineered AAVs for efficient noninvasive gene delivery to the central and peripheral nervous systems. Nat. Neurosci. 20, 1172–1179 (2017).

34. Challis, R. C. et al. Systemic AAV vectors for widespread and targeted gene delivery in rodents. Nat. Protoc. https://doi.org/10.1038/s41596-018-0097-3 (2019).

35. Froula, J. M. et al. α-Synuclein fibril-induced paradoxical structural and functional defects in hippocampal neurons. Acta Neuropathol. Commun. 6, 35 (2018).

36. Boesmans, W., Hao, M. M. & Berghe, P. V. Optical tools to investigate cellular activity in the intestinal wall. J. Neurogastroenterol. Motil. 21, 337–351 (2015).

37. Treweek, J. B. et al. Whole-body tissue stabilization and selective extractions via tissue–hydrogel hybrids for high-resolution intact circuit mapping and phenotyping. Nat. Protoc. 10, 1860–1896 (2015).

38. Reeve, A., Simcox, E. & Turnbull, D. Ageing and Parkinson’s disease: why is advancing age the biggest risk factor? Ageing Res. Rev. 14, 19–30 (2014).

39. Kordower, J. H. et al. Disease duration and the integrity of the nigrostriatal system in Parkinson’s disease. Brain J. Neurol 136, 2419–2431 (2013).

40. Salvatore, M. F., Pruett, B. S., Dempsey, C. & Fields, V. Comprehensive profiling of dopamine regulation in substantia nigra and ventral tegmental area. J. Vis. Exp. https://doi.org/10.3791/4171 (2012).

41. 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).

42. Tanner, C. M. et al. Rotenone, paraquat, and Parkinson’s disease. Environ. Health Perspect. 119, 866–872 (2011).

43. Rosenbloom, B. et al. The incidence of parkinsonism in patients with type 1 Gaucher disease: data from the ICGG Gaucher Registry. Blood Cells Mol. Dis. 46, 95–102 (2011).

44. Sidransky, E. & Lopez, G. The link between the GBA gene and parkinsonism. Lancet Neurol. 11, 986–998 (2012).

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

46. Whitton, P. S. Inflammation as a causative factor in the aetiology of Parkinson’s disease. Br. J. Pharmacol. 150, 963–976 (2009).

47. Neunlist, M. et al. Enteric glial cells: recent developments and future directions. Gastroenterology 147, 1230–1237 (2014).

48. Chandra, R., Hiniker, A., Kuo, Y.-M., Nussbaum, R. L. & Liddle, R. A. α-Synuclein in gut endocrine cells and its implications for Parkinson’s disease. JCI Insight 2, e92295 (2017).

49. Douglas, P. M. & Dillin, A. Protein homeostasis and aging in neurodegeneration. J. Cell Biol. 190, 719–729 (2010).

50. Fox, E. A., Phillips, R. J., Martinson, F. A., Baronowsky, E. A. & Powley, T. L. Vagal afferent innervation of smooth muscle in the stomach and duodenum of the mouse: morphology and topography. J. Comp. Neurol. 428, 558–576 (2000).

51. Rockenstein, E. et al. Differential neuropathological alterations in transgenic mice expressing alpha-synuclein from the platelet-derived growth factor and Thy-1 promoters. J. Neurosci. Res. 68, 568–578 (2002).

52. Li, Z. et al. Essential roles of enteric neuronal serotonin in gastrointestinal motility and the development/survival of enteric dopaminergic neurons. J. Neurosci. 31, 8998–9009 (2011).

53. Fleming, S. M., Ekhator, O. R. & Ghisays, V. Assessment of sensorimotor function in mouse mods of Parkinson’s disease. J. Vis. Exp. https://doi.org/10.3791/50303 (2013).

54. Deacon, R. M. J. Measuring the strength of mice. J. Vis. Exp. https://doi.org/10.3791/2610 (2013).

55. Bannon, A. W. & Malmberg, A. B. Models of nociception: hot-plate, tail-flick, and formalin tests in rodents. Curr. Protoc. Neurosci. 41, 8.9.1–8.9.16 (2007).