The vermiform appendix impacts the risk of developing Parkinson’s disease
Science Translational Medicine • 31 Oct 2018 • Vol 10, Issue 465 • DOI: 10.1126/scitranslmed.aar5280
The benefits of a missing appendix
Misfolded α-synuclein is a pathological hallmark of Parkinson’s disease (PD). Killinger et al. now report that the human appendix contains an abundance of misfolded α-synuclein and that removal of the appendix decreased the risk of developing PD. The appendix of both PD cases and healthy individuals contained abnormally cleaved and aggregated forms of α-synuclein, analogous to those found in postmortem brain tissue from patients with PD. Furthermore, α-synuclein derived from the appendix seeded rapid aggregation of recombinant α-synuclein in vitro. In two large-scale epidemiological studies, the authors demonstrated that an appendectomy occurring decades prior reduced the risk of developing PD, suggesting that the appendix may be implicated in PD initiation.
Abstract
The pathogenesis of Parkinson’s disease (PD) involves the accumulation of aggregated α-synuclein, which has been suggested to begin in the gastrointestinal tract. Here, we determined the capacity of the appendix to modify PD risk and influence pathogenesis. In two independent epidemiological datasets, involving more than 1.6 million individuals and over 91 million person-years, we observed that removal of the appendix decades before PD onset was associated with a lower risk for PD, particularly for individuals living in rural areas, and delayed the age of PD onset. We also found that the healthy human appendix contained intraneuronal α-synuclein aggregates and an abundance of PD pathology–associated α-synuclein truncation products that are known to accumulate in Lewy bodies, the pathological hallmark of PD. Lysates of human appendix tissue induced the rapid cleavage and oligomerization of full-length recombinant α-synuclein. Together, we propose that the normal human appendix contains pathogenic forms of α-synuclein that affect the risk of developing PD.
Get full access to this article
View all available purchase options and get full access to this article.
Already a Subscriber?Sign In
Supplementary Material
Summary
Materials and Methods
Fig. S1. Age of PD onset in individuals with and without a family history of PD in the PPMI data.
Fig. S2. An appendectomy delays the age of PD onset in individuals with a family history of PD that is not explained by genetic risk factors of PD.
Fig. S3. Validation of proteinase K digestion protocol in the human appendix used to assess aggregated α-synuclein.
Fig. S4. Evaluation of α-synuclein proteolysis under different tissue processing conditions.
Fig. S5. Extraction of detergent-soluble and -insoluble α-synuclein from appendix and brain tissue.
Fig. S6. Active cleavage of α-synuclein in the in vitro shaking assay with appendix tissue lysates.
Fig. S7. Effect of protease inhibition on α-synuclein cleavage and aggregation induced by appendix lysates.
Fig. S8. Identification of α-synuclein using TD-MS.
Fig. S9. Schematic of proposed model for the contributions of the vermiform appendix to PD.
Table S1. Characteristics of study samples from the SNPR.
Table S2. Appendectomy in relation to age of PD onset for patients with PD in the SNPR study.
Table S3. Incidence of PD in males and females living in rural and urban areas, SNPR study.
Table S4. Demographic and clinical information of patients with PD in the PPMI.
Table S5. Appendectomy in relation to age of PD onset for patients with PD in PPMI.
Table S6. PD age of onset is delayed in individuals with an appendectomy but not in individuals with non-GI immune conditions or other surgeries.
Table S7. Patients who had an appendectomy 30 or more years before PD do not show changes in PD symptom severity, as measured by the Hoehn and Yahr scale and UPDRS.
Table S8. α-Synuclein aggregates are detected in the appendix of both young and older adult individuals and are present in normal and inflamed appendix.
Table S9. Demographic and clinical information of sample sets used in PPMI study.
Table S10. Appendectomy delays age of PD onset in patients with de novo PD of PPMI.
Data file S1. Source data for biochemical assays.
Resources
REFERENCES AND NOTES
1
R. B. Postuma, D. Berg, M. Stern, W. Poewe, C. W. Olanow, W. Oertel, J. Obeso, K. Marek, I. Litvan, A. E. Lang, G. Halliday, C. G. Goetz, T. Gasser, B. Dubois, P. Chan, B. R. Bloem, C. H. Adler, G. Deuschl, MDS clinical diagnostic criteria for Parkinson’s disease. Mov. Disord. 30, 1591–1601 (2015).
2
J. M. Fearnley, A. J. Lees, Ageing and Parkinson’s disease: Substantia nigra regional selectivity. Brain 114 (Pt. 5), 2283–2301 (1991).
3
H. Chen, E. J. Zhao, W. Zhang, Y. Lu, R. Liu, X. Huang, A. J. Ciesielski-Jones, M. A. Justice, D. S. Cousins, S. Peddada, Meta-analyses on prevalence of selected Parkinson’s nonmotor symptoms before and after diagnosis. Transl. Neurodegener. 4, 1 (2015).
4
R. Savica, J. M. Carlin, B. R. Grossardt, J. H. Bower, J. E. Ahlskog, D. M. Maraganore, A. E. Bharucha, W. A. Rocca, Medical records documentation of constipation preceding Parkinson disease: A case-control study. Neurology 73, 1752–1758 (2009).
5
M. G. Stokholm, E. H. Danielsen, S. J. Hamilton-Dutoit, P. Borghammer, Pathological α-synuclein in gastrointestinal tissues from prodromal Parkinson disease patients. Ann. Neurol. 79, 940–949 (2016).
6
M. Barrenschee, D. Zorenkov, M. Böttner, C. Lange, F. Cossais, A. B. Scharf, G. Deuschl, S. A. Schneider, M. Ellrichmann, A. Fritscher-Ravens, T. Wedel, Distinct pattern of enteric phospho-alpha-synuclein aggregates and gene expression profiles in patients with Parkinson’s disease. Acta Neuropathol. Commun. 5, 1 (2017).
7
T. G. Beach, A. G. Corbille, F. Letournel, J. H. Kordower, T. Kremer, D. G. Munoz, A. Intorcia, J. Hentz, C. H. Adler, L. I. Sue, J. Walker, G. Serrano, P. Derkinderen, Multicenter assessment of immunohistochemical methods for pathological alpha-synuclein in sigmoid colon of autopsied Parkinson’s disease and control subjects. J. Parkinsons Dis. 6, 761–770 (2016).
8
A.-G. Corbillé, F. Letournel, J. H. Kordower, J. Lee, E. Shanes, M. Neunlist, D. G. Munoz, P. Derkinderen, T. G. Beach, Evaluation of alpha-synuclein immunohistochemical methods for the detection of Lewy-type synucleinopathy in gastrointestinal biopsies. Acta Neuropathol. Commun. 4, 35 (2016).
9
D. Hilton, M. Stephens, L. Kirk, P. Edwards, R. Potter, J. Zajicek, E. Broughton, H. Hagan, C. Carroll, Accumulation of α-synuclein in the bowel of patients in the pre-clinical phase of Parkinson’s disease. Acta Neuropathol. 127, 235–241 (2014).
10
C. H. Hawkes, K. Del Tredici, H. Braak, Parkinson’s disease: A dual-hit hypothesis. Neuropathol. Appl. Neurobiol. 33, 599–614 (2007).
11
L. A. Volpicelli-Daley, K. C. Luk, T. P. Patel, S. A. Tanik, D. M. Riddle, A. Stieber, D. F. Meaney, J. Q. Trojanowski, V. M.-Y. Lee, Exogenous α-synuclein fibrils induce Lewy body pathology leading to synaptic dysfunction and neuron death. Neuron 72, 57–71 (2011).
12
X. Mao, M. T. Ou, S. S. Karuppagounder, T.-I. Kam, X. Yin, Y. Xiong, P. Ge, G. E. Umanah, S. Brahmachari, J.-H. Shin, H. C. Kang, J. Zhang, J. Xu, R. Chen, H. Park, S. A. Andrabi, S. U. Kang, R. A. Gonçalves, Y. Liang, S. Zhang, C. Qi, S. Lam, J. A. Keiler, J. Tyson, D. Kim, N. Panicker, S. P. Yun, C. J. Workman, D. A. Vignali, V. L. Dawson, H. S. Ko, T. M. Dawson, Pathological α-synuclein transmission initiated by binding lymphocyte-activation gene 3. Science 353, aah3374 (2016).
13
B. Liu, F. Fang, N. L. Pedersen, A. Tillander, J. F. Ludvigsson, A. Ekbom, P. Svenningsson, H. Chen, K. Wirdefeldt, Vagotomy and Parkinson disease: A Swedish register-based matched-cohort study. Neurology 88, 1996–2002 (2017).
14
E. Svensson, E. Horvath-Puho, R. W. Thomsen, J. C. Djurhuus, L. Pedersen, P. Borghammer, H. T. Sorensen, Vagotomy and subsequent risk of Parkinson’s disease. Ann. Neurol. 78, 522–529 (2015).
15
O.-B. Tysnes, L. Kenborg, K. Herlofson, M. Steding-Jessen, A. Horn, J. H. Olsen, H. Reichmann, Does vagotomy reduce the risk of Parkinson’s disease? Ann. Neurol. 78, 1011–1012 (2015).
16
S. Holmqvist, O. Chutna, L. Bousset, P. Aldrin-Kirk, W. Li, T. Björklund, Z.-Y. Wang, L. Roybon, R. Melki, J.-Y. Li, Direct evidence of Parkinson pathology spread from the gastrointestinal tract to the brain in rats. Acta Neuropathol. 128, 805–820 (2014).
17
A. Ulusoy, R. Rusconi, B. I. Pérez-Revuelta, R. E. Musgrove, M. Helwig, B. Winzen-Reichert, D. A. Di Monte, Caudo-rostral brain spreading of α-synuclein through vagal connections. EMBO Mol. Med. 5, 1119–1127 (2013).
18
N. P. Visanji, P. L. Brooks, L.-N. Hazrati, A. E. Lang, The prion hypothesis in Parkinson’s disease: Braak to the future. Acta Neuropathol. Commun. 1, 2 (2013).
19
T. R. Sampson, J. W. Debelius, T. Thron, S. Janssen, G. G. Shastri, Z. E. Ilhan, C. Challis, C. E. Schretter, S. Rocha, V. Gradinaru, M.-F. Chesselet, A. Keshavarzian, K. M. Shannon, R. Krajmalnik-Brown, P. Wittung-Stafshede, R. Knight, S. K. Mazmanian, Gut microbiota regulate motor deficits and neuroinflammation in a model of Parkinson’s disease. Cell 167, 1469–1480.e12 (2016).
20
K. Knudsen, T. D. Fedorova, A. K. Hansen, M. Sommerauer, M. Otto, K. B. Svendsen, A. Nahimi, M. G. Stokholm, N. Pavese, C. P. Beier, D. J. Brooks, P. Borghammer, In-vivo staging of pathology in REM sleep behaviour disorder: A multimodality imaging case-control study. Lancet Neurol. 17, 618–628 (2018).
21
F. Pan-Montojo, M. Schwarz, C. Winkler, M. Arnhold, G. A. O’Sullivan, A. Pal, J. Said, G. Marsico, J.-M. Verbavatz, M. Rodrigo-Angulo, G. Gille, R. H. W. Funk, H. Reichmann, Environmental toxins trigger PD-like progression via increased alpha-synuclein release from enteric neurons in mice. Sci. Rep. 2, 898 (2012).
22
A. Keshavarzian, S. J. Green, P. A. Engen, R. M. Voigt, A. Naqib, C. B. Forsyth, E. Mutlu, K. M. Shannon, Colonic bacterial composition in Parkinson’s disease. Mov. Disord. 30, 1351–1360 (2015).
23
E. Stolzenberg, D. Berry, D. Yang, E. Y. Lee, A. Kroemer, S. Kaufman, G. C. L. Wong, J. J. Oppenheim, S. Sen, T. Fishbein, A. Bax, B. Harris, D. Barbut, M. A. Zasloff, A role for neuronal alpha-synuclein in gastrointestinal immunity. J. Innate Immun. 9, 456–463 (2017).
24
M. T. Gray, D. G. Munoz, D. A. Gray, M. G. Schlossmacher, J. M. Woulfe, Alpha-synuclein in the appendiceal mucosa of neurologically intact subjects. Mov. Disord. 29, 991–998 (2014).
25
A. Zahid, The vermiform appendix: Not a useless organ. J. Coll. Physicians Surg. Pak. 14, 256–258 (2004).
26
K. Masahata, E. Umemoto, H. Kayama, M. Kotani, S. Nakamura, T. Kurakawa, J. Kikuta, K. Gotoh, D. Motooka, S. Sato, T. Higuchi, Y. Baba, T. Kurosaki, M. Kinoshita, Y. Shimada, T. Kimura, R. Okumura, A. Takeda, M. Tajima, O. Yoshie, M. Fukuzawa, H. Kiyono, S. Fagarasan, T. Iida, M. Ishii, K. Takeda, Generation of colonic IgA-secreting cells in the caecal patch. Nat. Commun. 5, 3704 (2014).
27
K. C. Luk, C. Song, P. O’Brien, A. Stieber, J. R. Branch, K. R. Brunden, J. Q. Trojanowski, V. M.-Y. Lee, Exogenous α-synuclein fibrils seed the formation of Lewy body-like intracellular inclusions in cultured cells. Proc. Natl. Acad. Sci. U.S.A. 106, 20051–20056 (2009).
28
B. I. Giasson, I. V. Murray, J. Q. Trojanowski, V. M.-Y. Lee, A hydrophobic stretch of 12 amino acid residues in the middle of α-synuclein is essential for filament assembly. J. Biol. Chem. 276, 2380–2386 (2001).
29
R. A. Crowther, R. Jakes, M. G. Spillantini, M. Goedert, Synthetic filaments assembled from C-terminally truncated α-synuclein. FEBS Lett. 436, 309–312 (1998).
30
I. V. Y. Murray, B. I. Giasson, S. M. Quinn, V. Koppaka, P. H. Axelsen, H. Ischiropoulos, J. Q. Trojanowski, V. M.-Y. Lee, Role of α-synuclein carboxy-terminus on fibril formation in vitro. Biochemistry 42, 8530–8540 (2003).
31
M. Baba, S. Nakajo, P. H. Tu, T. Tomita, K. Nakaya, V. M. Lee, J. Q. Trojanowski, T. Iwatsubo, Aggregation of alpha-synuclein in Lewy bodies of sporadic Parkinson’s disease and dementia with Lewy bodies. Am. J. Pathol. 152, 879–884 (1998).
32
W. Li, N. West, E. Colla, O. Pletnikova, J. C. Troncoso, L. Marsh, T. M. Dawson, P. Jäkälä, T. Hartmann, D. L. Price, M. K. Lee, Aggregation promoting C-terminal truncation of α-synuclein is a normal cellular process and is enhanced by the familial Parkinson’s disease-linked mutations. Proc. Natl. Acad. Sci. U.S.A. 102, 2162–2167 (2005).
33
D.-H. Choi, Y.-J. Kim, Y.-G. Kim, T. H. Joh, M. F. Beal, Y.-S. Kim, Role of matrix metalloproteinase 3-mediated α-synuclein cleavage in dopaminergic cell death. J. Biol. Chem. 286, 14168–14177 (2011).
34
W. Wang, L. T. T. Nguyen, C. Burlak, F. Chegini, F. Guo, T. Chataway, S. Ju, O. S. Fisher, D. W. Miller, D. Datta, F. Wu, C.-X. Wu, A. Landeru, J. A. Wells, M. R. Cookson, M. B. Boxer, C. J. Thomas, W. P. Gai, D. Ringe, G. A. Petsko, Q. Q. Hoang, Caspase-1 causes truncation and aggregation of the Parkinson’s disease-associated protein α-synuclein. Proc. Natl. Acad. Sci. U.S.A. 113, 9587–9592 (2016).
35
Z. Zhang, S. S. Kang, X. Liu, E. H. Ahn, Z. Zhang, L. He, P. M. Iuvone, D. M. Duong, N. T. Seyfried, M. J. Benskey, F. P. Manfredsson, L. Jin, Y. E. Sun, J.-Z. Wang, K. Ye, Asparagine endopeptidase cleaves α-synuclein and mediates pathologic activities in Parkinson’s disease. Nat. Struct. Mol. Biol. 24, 632–642 (2017).
36
J. M. Gorell, C. C. Johnson, B. A. Rybicki, E. L. Peterson, R. J. Richardson, The risk of Parkinson’s disease with exposure to pesticides, farming, well water, and rural living. Neurology 50, 1346–1350 (1998).
37
R. Betarbet, T. B. Sherer, G. MacKenzie, M. Garcia-Osuna, A. V. Panov, J. T. Greenamyre, Chronic systemic pesticide exposure reproduces features of Parkinson’s disease. Nat. Neurosci. 3, 1301–1306 (2000).
38
R. Savica, W. A. Rocca, J. E. Ahlskog, When does Parkinson disease start? Arch. Neurol. 67, 798–801 (2010).
39
M. Neumann, V. Müller, H. A. Kretzschmar, C. Haass, P. J. Kahle, Regional distribution of proteinase K-resistant α-synuclein correlates with Lewy body disease stage. J. Neuropathol. Exp. Neurol. 63, 1225–1235 (2004).
40
H.-J. Lee, S.-J. Lee, Characterization of cytoplasmic α-synuclein aggregates. Fibril formation is tightly linked to the inclusion-forming process in cells. J. Biol. Chem. 277, 48976–48983 (2002).
41
I. F. Tsigelny, L. Crews, P. Desplats, G. M. Shaked, Y. Sharikov, H. Mizuno, B. Spencer, E. Rockenstein, M. Trejo, O. Platoshyn, J. X.-J. Yuan, E. Masliah, Mechanisms of hybrid oligomer formation in the pathogenesis of combined Alzheimer’s and Parkinson’s diseases. PLOS ONE 3, e3135 (2008).
42
J. Zhou, M. Broe, Y. Huang, J. P. Anderson, W.-P. Gai, E. A. Milward, M. Porritt, D. Howells, A. J. Hughes, X. Wang, G. M. Halliday, Changes in the solubility and phosphorylation of α-synuclein over the course of Parkinson’s disease. Acta Neuropathol. 121, 695–704 (2011).
43
A. Mendes, A. Gonçalves, N. Vila-Chã, I. Moreira, J. Fernandes, J. Dámasio, A. Teixeira-Pinto, R. Taipa, A. B. Lima, S. Cavaco, Appendectomy may delay Parkinson’s disease onset. Mov. Disord. 30, 1404–1407 (2015).
44
C. Marras, A. E. Lang, P. C. Austin, C. Lau, D. R. Urbach, Appendectomy in mid and later life and risk of Parkinson’s disease: A population-based study. Mov. Disord. 31, 1243–1247 (2016).
45
R. Yilmaz, E. Bayram, C. Ulukan, M. K. Altinok, M. C. Akbostanci, Appendectomy history is not related to Parkinson’s disease. J. Parkinsons Dis. 7, 347–352 (2017).
46
E. Svensson, E. Horváth-Puhó, M. G. Stokholm, H. T. Sørensen, V. W. Henderson, P. Borghammer, Appendectomy and risk of Parkinson’s disease: A nationwide cohort study with more than 10 years of follow-up. Mov. Disord. 31, 1918–1922 (2016).
47
A. Barbeau, M. Roy, G. Bernier, G. Campanella, S. Paris, Ecogenetics of Parkinson’s disease: Prevalence and environmental aspects in rural areas. Can. J. Neurol. Sci. 14, 36–41 (1987).
48
E. Angot, J. A. Steiner, C. Hansen, J. Y. Li, P. Brundin, Are synucleinopathies prion-like disorders? Lancet Neurol. 9, 1128–1138 (2010).
49
H. Braak, E. Braak, Pathoanatomy of Parkinson’s disease. J. Neurol. 247 (suppl. 2), II3–II10 (2000).
50
T. G. Beach, C. H. Adler, L. I. Sue, L. Vedders, L. Lue, C. L. White III, H. Akiyama, J. N. Caviness, H. A. Shill, M. N. Sabbagh, D. G. Walker; Arizona Parkinson’s Disease Consortium, Multi-organ distribution of phosphorylated α-synuclein histopathology in subjects with Lewy body disorders. Acta Neuropathol. 119, 689–702 (2010).
51
T. Lebouvier, T. Chaumette, P. Damier, E. Coron, Y. Touchefeu, S. Vrignaud, P. Naveilhan, J. P. Galmiche, S. Bruley des Varannes, P. Derkinderen, M. Neunlist, Pathological lesions in colonic biopsies during Parkinson’s disease. Gut 57, 1741–1743 (2008).
52
K. Wakabayashi, H. Takahashi, S. Takeda, E. Ohama, F. Ikuta, Parkinson’s disease: The presence of Lewy bodies in Auerbach’s and Meissner’s plexuses. Acta Neuropathol. 76, 217–221 (1988).
53
D. Games, E. Valera, B. Spencer, E. Rockenstein, M. Mante, A. Adame, C. Patrick, K. Ubhi, S. Nuber, P. Sacayon, W. Zago, P. Seubert, R. Barbour, D. Schenk, E. Masliah, Reducing C-terminal-truncated alpha-synuclein by immunotherapy attenuates neurodegeneration and propagation in Parkinson’s disease-like models. J. Neurosci. 34, 9441–9454 (2014).
54
J. F. Kellie, R. E. Higgs, J. W. Ryder, A. Major, T. G. Beach, C. H. Adler, K. Merchant, M. D. Knierman, Quantitative measurement of intact alpha-synuclein proteoforms from post-mortem control and Parkinson’s disease brain tissue by intact protein mass spectrometry. Sci. Rep. 4, 5797 (2014).
55
D. Grassi, S. Howard, M. Zhou, N. Diaz-Perez, N. T. Urban, D. Guerrero-Given, N. Kamasawa, L. A. Volpicelli-Daley, P. LoGrasso, C. I. Lasmézas, Identification of a highly neurotoxic α-synuclein species inducing mitochondrial damage and mitophagy in Parkinson’s disease. Proc. Natl. Acad. Sci. U.S.A. 115, E2634–E2643 (2018).
56
A. Ulusoy, F. Febbraro, P. H. Jensen, D. Kirik, M. Romero-Ramos, Co-expression of C-terminal truncated alpha-synuclein enhances full-length alpha-synuclein-induced pathology. Eur. J. Neurosci. 32, 409–422 (2010).
57
T. Bartels, L. S. Ahlstrom, A. Leftin, F. Kamp, C. Haass, M. F. Brown, K. Beyer, The N-terminus of the intrinsically disordered protein α-synuclein triggers membrane binding and helix folding. Biophys. J. 99, 2116–2124 (2010).
58
M. Terada, G. Suzuki, T. Nonaka, F. Kametani, A. Tamaoka, M. Hasegawa, The effect of truncation on prion-like properties of α-synuclein. J. Biol. Chem. 293, 13910–13920 (2018).
59
B. M. Dufty, L. R. Warner, S. T. Hou, S. X. Jiang, T. Gomez-Isla, K. M. Leenhouts, J. T. Oxford, M. B. Feany, E. Masliah, T. T. Rohn, Calpain-cleavage of α-synuclein: Connecting proteolytic processing to disease-linked aggregation. Am. J. Pathol. 170, 1725–1738 (2007).
60
W. Peelaerts, L. Bousset, A. Van der Perren, A. Moskalyuk, R. Pulizzi, M. Giugliano, C. Van den Haute, R. Melki, V. Baekelandt, α-Synuclein strains cause distinct synucleinopathies after local and systemic administration. Nature 522, 340–344 (2015).
61
P. Borghammer, How does Parkinson’s disease begin? Perspectives on neuroanatomical pathways, prions, and histology. Mov. Disord. 33, 48–57 (2018).
62
A. L. Feldman, A. L. V. Johansson, M. Gatz, M. Flensburg, G. M. Petzinger, H. Widner, M. F. Lew, N. L. Pedersen, K. Wirdefeldt, Accuracy and sensitivity of Parkinsonian disorder diagnoses in two Swedish national health registers. Neuroepidemiology 38, 186–193 (2012).
63
Parkinson Progression Marker Initiative, The Parkinson Progression Marker Initiative (PPMI). Prog. Neurobiol. 95, 629–635 (2011).
64
M. E. Short, R. Z. Goetzel, X. Pei, M. J. Tabrizi, R. J. Ozminkowski, T. B. Gibson, D. M. Dejoy, M. G. Wilson, How accurate are self-reports? Analysis of self-reported health care utilization and absence when compared with administrative data. J. Occup. Environ. Med. 51, 786–796 (2009).
65
W. Richards, D. Watson, G. Lynch, G. W. Reed, D. Olsen, A. Spaw, W. Holcomb, M. Frexes-Steed, R. Goldstein, K. Sharp, A review of the results of laparoscopic versus open appendectomy. Surg. Gynecol. Obstet. 177, 473–480 (1993).
66
M. Ferris, S. Quan, B. S. Kaplan, N. Molodecky, C. G. Ball, G. W. Chernoff, N. Bhala, S. Ghosh, E. Dixon, S. Ng, G. G. Kaplan, The global incidence of appendicitis: A systematic review of population-based studies. Ann. Surg. 266, 237–241 (2017).
67
D. M. Hardin Jr., Acute appendicitis: Review and update. Am. Fam. Physician 60, 2027–2034 (1999).
68
B. Stewart, P. Khanduri, C. McCord, M. Ohene-Yeboah, S. Uranues, F. Vega Rivera, C. Mock, Global disease burden of conditions requiring emergency surgery. Br. J. Surg. 101, e9–e22 (2014).
69
M. N. Khan, T. Fayyad, T. D. Cecil, B. J. Moran, Laparoscopic versus open appendectomy: The risk of postoperative infectious complications. JSLS 11, 363–367 (2007).
70
U. Guller, S. Hervey, H. Purves, L. H. Muhlbaier, E. D. Peterson, S. Eubanks, R. Pietrobon, Laparoscopic versus open appendectomy: Outcomes comparison based on a large administrative database. Ann. Surg. 239, 43–52 (2004).
71
O. Mentes, M. Eryilmaz, A. Harlak, T. Ozer, M. Balkan, O. Kozak, T. Tufan, Can d-dimer become a new diagnostic parameter for acute appendicitis? Am. J. Emerg. Med. 27, 765–769 (2009).
72
A. Lionnet, L. Leclair-Visonneau, M. Neunlist, S. Murayama, M. Takao, C. H. Adler, P. Derkinderen, T. G. Beach, Does Parkinson’s disease start in the gut? Acta Neuropathol. 135, 1–12 (2018).
73
K. Y. Hui, H. Fernandez-Hernandez, J. Hu, A. Schaffner, N. Pankratz, N.-Y. Hsu, L.-S. Chuang, S. Carmi, N. Villaverde, X. Li, M. Rivas, A. P. Levine, X. Bao, P. R. Labrias, T. Haritunians, D. Ruane, K. Gettler, E. Chen, D. Li, E. R. Schiff, N. Pontikos, N. Barzilai, S. R. Brant, S. Bressman, A. S. Cheifetz, L. N. Clark, M. J. Daly, R. J. Desnick, R. H. Duerr, S. Katz, T. Lencz, R. H. Myers, H. Ostrer, L. Ozelius, H. Payami, Y. Peter, J. D. Rioux, A. W. Segal, W. K. Scott, M. S. Silverberg, J. M. Vance, I. Ubarretxena-Belandia, T. Foroud, G. Atzmon, I. Pe’er, Y. Ioannou, D. P. B. McGovern, Z. Yue, E. E. Schadt, J. H. Cho, I. Peter, Functional variants in the LRRK2 gene confer shared effects on risk for Crohn’s disease and Parkinson’s disease. Sci. Transl. Med. 10, eaai7795 (2018).
74
I. Peter, M. Dubinsky, S. Bressman, A. Park, C. Lu, N. Chen, A. Wang, Anti-tumor necrosis factor therapy and incidence of Parkinson disease among patients with inflammatory bowel disease. JAMA Neurol. 75, 939–946 (2018).
75
R. E. Andersson, G. Olaison, C. Tysk, A. Ekbom, Appendectomy and protection against ulcerative colitis. N. Engl. J. Med. 344, 808–814 (2001).
76
P. Brundin, K. D. Dave, J. H. Kordower, Therapeutic approaches to target alpha-synuclein pathology. Exp. Neurol. 298 (Pt. B), 225–235 (2017).
77
O. M. El-Agnaf, K. E. Paleologou, B. Greer, A. M. Abogrein, J. E. King, S. A. Salem, N. J. Fullwood, F. E. Benson, R. Hewitt, K. J. Ford, F. L. Martin, P. Harriott, M. R. Cookson, D. Allsop, A strategy for designing inhibitors of α-synuclein aggregation and toxicity as a novel treatment for Parkinson’s disease and related disorders. FASEB J. 18, 1315–1317 (2004).
78
S. Zucker, J. Cao, W.-T. Chen, Critical appraisal of the use of matrix metalloproteinase inhibitors in cancer treatment. Oncogene 19, 6642–6650 (2000).
79
E. L. Beatman, A. Massey, K. D. Shives, K. S. Burrack, M. Chamanian, T. E. Morrison, J. D. Beckham, Alpha-synuclein expression restricts RNA viral infections in the brain. J. Virol. 90, 2767–2782 (2015).
80
S. G. Chen, V. Stribinskis, M. J. Rane, D. R. Demuth, E. Gozal, A. M. Roberts, R. Jagadapillai, R. Liu, K. Choe, B. Shivakumar, F. Son, S. Jin, R. Kerber, A. Adame, E. Masliah, R. P. Friedland, Exposure to the functional bacterial amyloid protein curli enhances alpha-synuclein aggregation in aged Fischer 344 rats and Caenorhabditis elegans. Sci. Rep. 6, 34477 (2016).
81
F. Scheperjans, V. Aho, P. A. B. Pereira, K. Koskinen, L. Paulin, E. Pekkonen, E. Haapaniemi, S. Kaakkola, J. Eerola-Rautio, M. Pohja, E. Kinnunen, K. Murros, P. Auvinen, Gut microbiota are related to Parkinson’s disease and clinical phenotype. Mov. Disord. 30, 350–358 (2015).
82
N. L. Rey, J. A. Steiner, N. Maroof, K. C. Luk, Z. Madaj, J. Q. Trojanowski, V. M.-Y. Lee, P. Brundin, Widespread transneuronal propagation of α-synucleinopathy triggered in olfactory bulb mimics prodromal Parkinson’s disease. J. Exp. Med. 213, 1759–1778 (2016).
83
T. G. Beach, C. H. Adler, L. Lue, L. I. Sue, J. Bachalakuri, J. Henry-Watson, J. Sasse, S. Boyer, S. Shirohi, R. Brooks, J. Eschbacher, C. L. White III, H. Akiyama, J. Caviness, H. A. Shill, D. J. Connor, M. N. Sabbagh, D. G. Walker; Arizona Parkinson’s Disease Consortium, Unified staging system for Lewy body disorders: Correlation with nigrostriatal degeneration, cognitive impairment and motor dysfunction. Acta Neuropathol. 117, 613–634 (2009).
84
Socialstyrelsen, The National Patient Register; www.socialstyrelsen.se/register/halsodataregister/patientregistret/inenglish (2017).
85
J. F. Ludvigsson, E. Andersson, A. Ekbom, M. Feychting, J.-L. Kim, C. Reuterwall, M. Heurgren, P. O. Olausson, External review and validation of the Swedish national inpatient register. BMC Public Health 11, 450 (2011).
86
D. Ho, K. Imai, G. King, E. A. Stuart, MatchIt: Nonparametric preprocessing for parametric causal inference. J. Stat Softw. 42, 1–28 (2011).
87
Organisation for Economic Co-operation and Development (OECD), Functional urban areas in OECD countries: Sweden; www.oecd.org/cfe/regional-policy/functional-urban-areas-all-sweden.pdf (2016).
88
B. George, S. Seals, I. Aban, Survival analysis and regression models. J. Nucl. Cardiol. 21, 686–694 (2014).
89
T. Therneau, A Package for Survival Analysis in S. Version 2.38; https://CRAN.R-project.org/package=survival (2015).
90
R. G. Miller Jr., G. Gong, A. Munoz, Survival Analysis (John Wiley and Sons, 1981).
91
W. N. Venables, B. D. Ripley, Modern Applied Statistics with S (Springer-Verlag, ed. 4, 2002).
92
D. B. Friedman, Quantitative proteomics for two-dimensional gels using difference gel electrophoresis. Methods Mol. Biol. 367, 219–239 (2007).
93
R. H. Butt, J. R. Coorssen, Coomassie blue as a near-infrared fluorescent stain: A systematic comparison with Sypro Ruby for in-gel protein detection. Mol. Cell. Proteomics 12, 3834–3850 (2013).
94
R. Atarashi, K. Satoh, K. Sano, T. Fuse, N. Yamaguchi, D. Ishibashi, T. Matsubara, T. Nakagaki, H. Yamanaka, S. Shirabe, M. Yamada, H. Mizusawa, T. Kitamoto, G. Klug, A. McGlade, S. J. Collins, N. Nishida, Ultrasensitive human prion detection in cerebrospinal fluid by real-time quaking-induced conversion. Nat. Med. 17, 175–178 (2011).
95
D. Wessel, U. I. Flügge, A method for the quantitative recovery of protein in dilute solution in the presence of detergents and lipids. Anal. Biochem. 138, 141–143 (1984).
96
I. Ntai, T. K. Toby, R. D. LeDuc, N. L. Kelleher, A method for label-free, differential top-down proteomics. Methods Mol. Biol. 1410, 121–133 (2016).
Information & Authors
Information
Published In
Science Translational Medicine
Volume 10 | Issue 465
October 2018
October 2018
Copyright
Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
This is an article distributed under the terms of the Science Journals Default License.
Submission history
Received: 17 November 2017
Accepted: 8 June 2018
Acknowledgments
We thank J. Ma for providing purified human α-synuclein. We thank J. Saunders for technical assistance and C. DeHart for advice on mass spectrometry work. We thank Van Andel Research Institute core services including pathology and biorepository, confocal and quantitative imaging, and bioinformatics and biostatistics. Some data used in the preparation of this article were obtained from the PPMI database (www.ppmi-info.org/data). For up-to-date information on the study, visit www.ppmi-info.org. Funding: V.L. was supported by grants from the Alzheimer’s Society of Canada (1615), the Scottish Rite Charitable Foundation of Canada (15110), the Department of Defense (PD170089), and a Gibby & Friends vs. Parky award. L.B. was supported by a grant from the Michael J. Fox Foundation (14939). P.B. reports relevant grants from NIH (R01DC016519-01 and 5R21NS093993-02), Department of Defense (W81XWH-17-1-0534), The Michael J. Fox Foundation for Parkinson’s Research, and Cure Parkinson’s Trust. Mass spectrometry work was supported by the National Resource for Translational and Developmental Proteomics (P41 GM108569). PPMI, a public-private partnership, is funded by the Michael J. Fox Foundation for Parkinson’s Research and funding partners, including Abbvie, Allergan, Avid Radiopharmaceuticals, Biogen, BioLegend, Bristol-Myers Squibb, Denali, GE Healthcare, Genentech, GlaxoSmithKline, Lilly, Lundbeck, Merck, Meso Scale Discovery, Pfizer, Piramal, Roche, Sanofi Genzyme, Servier, Takeda, Teva, UCB, and Golub Capital. Author contributions: The study was designed and coordinated by V.L. V.L., B.A.K., and Z.M. designed the experiments within the study. B.A.K. performed the biochemical studies. Z.M. performed the epidemiological analyses, and H.C. reviewed these analyses. J.W.S. and P.M.T. performed the mass spectrometry analysis. A.J.H., N.R., and B.A.K. contributed to the immunohistochemistry experiments. Y.V. contributed to the PPMI data analysis. L.B. and D.L. contributed to the SNPR study. The manuscript was written by B.A.K., P.B., L.B., and V.L., and commented on by all authors. Competing interests: P.B. has received commercial support as a consultant from Renovo Neural, Roche, Teva, Lundbeck A/S, AbbVie, NeuroDerm, Fujifilm Cellular Dynamics, Living Cell Technologies, ClearView Healthcare, FCB Health, IOS Press Partners, Capital Technologies, and Axial Biotherapeutics. In addition, P.B. has received commercial support for grants/research from Renovo, Roche, Teva, and Lundbeck. P.B. has ownership interests in AcouSort AB. The other authors declare that they have no competing interests. Data and materials availability: Data used in the SNPR study can be obtained with ethical approval from the SNPR and SCB (www.socialstyrelsen.se/register/halsodataregister/patientregistret/inenglish). Data for the PPMI study can be obtained from www.ppmi-info.org. All other data associated with this study are in the paper or the Supplementary Materials.
Authors
Funding Information
National Institutes of Health: R01DC016519-01
National Institutes of Health: 5R21NS093993-02
Department of Defense: W81XWH-17-1-0534
Alzheimer’s Society of Canada: 16 15
The Michael J. Fox Foundation for Parkinson’s Research and Cure Parkinson’s Trust
National Resource for Translational and Developmental Proteomics: P41 GM108569
Metrics & Citations
Metrics
Article Usage
Altmetrics
Citations
Export citation
Select the format you want to export the citation of this publication.
Cited by
- Effects of α-Synuclein-Associated Post-Translational Modifications in Parkinson’s Disease, ACS Chemical Neuroscience, 12, 7, (1061-1071), (2021).https://doi.org/10.1021/acschemneuro.1c00028
- Increased Accumulation of α‐Synuclein in Inflamed Appendices of Parkinson's Disease Patients , Movement Disorders, 36, 8, (1911-1918), (2021).https://doi.org/10.1002/mds.28553
- Accumulation of alpha-synuclein within the liver, potential role in the clearance of brain pathology associated with Parkinson’s disease, Acta Neuropathologica Communications, 9, 1, (2021).https://doi.org/10.1186/s40478-021-01136-3
- Early constipation predicts faster dementia onset in Parkinson’s disease, npj Parkinson's Disease, 7, 1, (2021).https://doi.org/10.1038/s41531-021-00191-w
- Parkinson's disease and the gut: Models of an emerging relationship, Acta Biomaterialia, (2021).https://doi.org/10.1016/j.actbio.2021.03.071
- Vagus Nerve and Stomach Synucleinopathy in Parkinson’s Disease, Incidental Lewy Body Disease, and Normal Elderly Subjects: Evidence Against the “Body-First” Hypothesis, Journal of Parkinson's Disease, (1-11), (2021).https://doi.org/10.3233/JPD-212733
- Infection and Risk of Parkinson’s Disease, Journal of Parkinson's Disease, 11, 1, (31-43), (2021).https://doi.org/10.3233/JPD-202279
- Association of NO 2 and Other Air Pollution Exposures With the Risk of Parkinson Disease , JAMA Neurology, 78, 7, (800), (2021).https://doi.org/10.1001/jamaneurol.2021.1335
- Exosomes in Parkinson disease, Journal of Neurochemistry, 157, 3, (413-428), (2021).https://doi.org/10.1111/jnc.15288
- Disorders of the enteric nervous system — a holistic view, Nature Reviews Gastroenterology & Hepatology, 18, 6, (393-410), (2021).https://doi.org/10.1038/s41575-020-00385-2
- See more
Loading...
View Options
Get Access
Log in to view the full text
AAAS login provides access to Science for AAAS Members, and access to other journals in the Science family to users who have purchased individual subscriptions.
- Become a AAAS Member
- Activate your AAAS ID
- Purchase Access to Other Journals in the Science Family
- Account Help
Log in via OpenAthens.
Log in via Shibboleth.
More options
Register for free to read this article
As a service to the community, this article is available for free. Login or register for free to read this article.
View options
PDF format
Download this article as a PDF file
Download PDF