Skip to main content
Top
Published in: Clinical Autonomic Research 3/2016

Open Access 01-06-2016 | Research Article

Changes in the sympathetic innervation of the gut in rotenone treated mice as possible early biomarker for Parkinson’s disease

Authors: Mike Arnhold, Yanina Dening, Michaël Chopin, Esteban Arévalo, Mathias Schwarz, Heinz Reichmann, Gabriele Gille, Richard H. W. Funk, Francisco Pan-Montojo

Published in: Clinical Autonomic Research | Issue 3/2016

Login to get access

Abstract

Introduction

Involvement of the peripheral nervous system (PNS) is relatively common in Parkinson’s disease (PD) patients. PNS alterations appear early in the course of the disease and are responsible for some of the non-motor symptoms observed in PD patients. In previous studies, we have shown that environmental toxins can trigger the disease by acting on the enteric nervous system.

Material and methods

Here, we analyzed the effect of mitochondrial Complex I inhibition on sympathetic neuritis in vivo and sympathetic neurons in vitro. Combining in vivo imaging and protein expression profiling.

Results

we found that rotenone, a widely used mitochondrial Complex I inhibitor decreases the density of sympathetic neurites innervating the gut in vivo, while in vitro, it induces the redistribution of intracellular alpha-synuclein and neurite degeneration. Interestingly, sympathetic neurons are much more resistant to rotenone exposure than mesencephalic dopaminergic neurons.

Conclusion

Altogether, these results suggest that enteric sympathetic denervation could be an initial pre-motor alteration in PD progression that could be used as an early biomarker of the disease.
Appendix
Available only for authorised users
Literature
1.
go back to reference Braak H, Sastre M, Bohl JR, de Vos RA, Del Tredici K (2007) Parkinson’s disease: lesions in dorsal horn layer I, involvement of parasympathetic and sympathetic pre- and postganglionic neurons. Acta Neuropathol 113(4):421–429CrossRefPubMed Braak H, Sastre M, Bohl JR, de Vos RA, Del Tredici K (2007) Parkinson’s disease: lesions in dorsal horn layer I, involvement of parasympathetic and sympathetic pre- and postganglionic neurons. Acta Neuropathol 113(4):421–429CrossRefPubMed
2.
go back to reference Wakabayashi K, Takahashi H, Ohama E, Ikuta F (1990) Parkinson’s disease: an immunohistochemical study of Lewy body-containing neurons in the enteric nervous system. Acta Neuropathol 79(6):581–583CrossRefPubMed Wakabayashi K, Takahashi H, Ohama E, Ikuta F (1990) Parkinson’s disease: an immunohistochemical study of Lewy body-containing neurons in the enteric nervous system. Acta Neuropathol 79(6):581–583CrossRefPubMed
3.
go back to reference Wakabayashi K, Takahashi H (2006) Cellular pathology in multiple system atrophy. Neuropathology 26(4):338–345CrossRefPubMed Wakabayashi K, Takahashi H (2006) Cellular pathology in multiple system atrophy. Neuropathology 26(4):338–345CrossRefPubMed
4.
go back to reference Herzog E (1928) Histopathologische Veränderungen im Sympathicus und ihre Bedeutung. Dtsch Z Nervenheilk 107:75–80CrossRef Herzog E (1928) Histopathologische Veränderungen im Sympathicus und ihre Bedeutung. Dtsch Z Nervenheilk 107:75–80CrossRef
5.
go back to reference Wakabayashi K, Tanji K, Mori F, Takahashi H (2007) The Lewy body in Parkinson’s disease: molecules implicated in the formation and degradation of alpha-synuclein aggregates. Neuropathology 27(5):494–506CrossRefPubMed Wakabayashi K, Tanji K, Mori F, Takahashi H (2007) The Lewy body in Parkinson’s disease: molecules implicated in the formation and degradation of alpha-synuclein aggregates. Neuropathology 27(5):494–506CrossRefPubMed
6.
go back to reference Forno LS, Norville RL (1976) Ultrastructure of Lewy bodies in the stellate ganglion. Acta Neuropathol 34(3):183–197CrossRefPubMed Forno LS, Norville RL (1976) Ultrastructure of Lewy bodies in the stellate ganglion. Acta Neuropathol 34(3):183–197CrossRefPubMed
7.
go back to reference Wakabayashi K, Takahashi H (1997) Neuropathology of autonomic nervous system in Parkinson’s disease. Eur Neurol 38(Suppl 2):2–7CrossRefPubMed Wakabayashi K, Takahashi H (1997) Neuropathology of autonomic nervous system in Parkinson’s disease. Eur Neurol 38(Suppl 2):2–7CrossRefPubMed
8.
go back to reference Braak H, de Vos RA, Bohl J, Del Tredici K (2006) Gastric alpha-synuclein immunoreactive inclusions in Meissner’s and Auerbach’s plexuses in cases staged for Parkinson’s disease-related brain pathology. Neurosci Lett 396(1):67–72CrossRefPubMed Braak H, de Vos RA, Bohl J, Del Tredici K (2006) Gastric alpha-synuclein immunoreactive inclusions in Meissner’s and Auerbach’s plexuses in cases staged for Parkinson’s disease-related brain pathology. Neurosci Lett 396(1):67–72CrossRefPubMed
9.
go back to reference Braak H, Ghebremedhin E, Rub U, Bratzke H, Del Tredici K (2004) Stages in the development of Parkinson’s disease-related pathology. Cell Tissue Res 318(1):121–134CrossRefPubMed Braak H, Ghebremedhin E, Rub U, Bratzke H, Del Tredici K (2004) Stages in the development of Parkinson’s disease-related pathology. Cell Tissue Res 318(1):121–134CrossRefPubMed
10.
go back to reference Wolters E, Braak H (2006) Parkinson’s disease: premotor clinico-pathological correlations. J Neural Transm Suppl 70:309–319CrossRefPubMed Wolters E, Braak H (2006) Parkinson’s disease: premotor clinico-pathological correlations. J Neural Transm Suppl 70:309–319CrossRefPubMed
11.
go back to reference Amino T, Orimo S, Itoh Y, Takahashi A, Uchihara T, Mizusawa H (2005) Profound cardiac sympathetic denervation occurs in Parkinson disease. Brain Pathol 15(1):29–34CrossRefPubMed Amino T, Orimo S, Itoh Y, Takahashi A, Uchihara T, Mizusawa H (2005) Profound cardiac sympathetic denervation occurs in Parkinson disease. Brain Pathol 15(1):29–34CrossRefPubMed
12.
go back to reference Orimo S, Amino T, Itoh Y, Takahashi A, Kojo T, Uchihara T, Tsuchiya K, Mori F, Wakabayashi K, Takahashi H (2005) Cardiac sympathetic denervation precedes neuronal loss in the sympathetic ganglia in Lewy body disease. Acta Neuropathol 109(6):583–588CrossRefPubMed Orimo S, Amino T, Itoh Y, Takahashi A, Kojo T, Uchihara T, Tsuchiya K, Mori F, Wakabayashi K, Takahashi H (2005) Cardiac sympathetic denervation precedes neuronal loss in the sympathetic ganglia in Lewy body disease. Acta Neuropathol 109(6):583–588CrossRefPubMed
13.
go back to reference Tipre DN, Goldstein DS (2005) Cardiac and extracardiac sympathetic denervation in Parkinson’s disease with orthostatic hypotension and in pure autonomic failure. J Nucl Med 46(11):1775–1781PubMed Tipre DN, Goldstein DS (2005) Cardiac and extracardiac sympathetic denervation in Parkinson’s disease with orthostatic hypotension and in pure autonomic failure. J Nucl Med 46(11):1775–1781PubMed
14.
go back to reference Pan-Montojo FJ, Funk RH (2010) Oral administration of rotenone using a gavage and image analysis of alpha-synuclein inclusions in the enteric nervous system. J Vis Exp (44) Pan-Montojo FJ, Funk RH (2010) Oral administration of rotenone using a gavage and image analysis of alpha-synuclein inclusions in the enteric nervous system. J Vis Exp (44)
15.
go back to reference Pan-Montojo F, Schwarz M, Winkler C, Arnhold M, O’Sullivan GA, Pal A, Said J, Marsico G, Verbavatz JM, Rodrigo-Angulo M et al (2012) Environmental toxins trigger PD-like progression via increased alpha-synuclein release from enteric neurons in mice. Sci Rep 2:898CrossRefPubMedPubMedCentral Pan-Montojo F, Schwarz M, Winkler C, Arnhold M, O’Sullivan GA, Pal A, Said J, Marsico G, Verbavatz JM, Rodrigo-Angulo M et al (2012) Environmental toxins trigger PD-like progression via increased alpha-synuclein release from enteric neurons in mice. Sci Rep 2:898CrossRefPubMedPubMedCentral
16.
go back to reference Hawrot E, Patterson PH (1979) Long-term culture of dissociated sympathetic neurons. Methods Enzymol 58:574–584CrossRefPubMed Hawrot E, Patterson PH (1979) Long-term culture of dissociated sympathetic neurons. Methods Enzymol 58:574–584CrossRefPubMed
17.
go back to reference Davoren M, Herzog E, Casey A, Cottineau B, Chambers G, Byrne HJ, Lyng FM (2007) In vitro toxicity evaluation of single walled carbon nanotubes on human A549 lung cells. Toxicol In Vitro 21(3):438–448CrossRefPubMed Davoren M, Herzog E, Casey A, Cottineau B, Chambers G, Byrne HJ, Lyng FM (2007) In vitro toxicity evaluation of single walled carbon nanotubes on human A549 lung cells. Toxicol In Vitro 21(3):438–448CrossRefPubMed
18.
go back to reference Betarbet R, Sherer TB, MacKenzie G, Garcia-Osuna M, Panov AV, Greenamyre JT (2000) Chronic systemic pesticide exposure reproduces features of Parkinson’s disease. Nat Neurosci 3(12):1301–1306CrossRefPubMed Betarbet R, Sherer TB, MacKenzie G, Garcia-Osuna M, Panov AV, Greenamyre JT (2000) Chronic systemic pesticide exposure reproduces features of Parkinson’s disease. Nat Neurosci 3(12):1301–1306CrossRefPubMed
19.
go back to reference Sherer TB, Betarbet R, Testa CM, Seo BB, Richardson JR, Kim JH, Miller GW, Yagi T, Matsuno-Yagi A, Greenamyre JT (2003) Mechanism of toxicity in rotenone models of Parkinson’s disease. J Neurosci 23(34):10756–10764PubMed Sherer TB, Betarbet R, Testa CM, Seo BB, Richardson JR, Kim JH, Miller GW, Yagi T, Matsuno-Yagi A, Greenamyre JT (2003) Mechanism of toxicity in rotenone models of Parkinson’s disease. J Neurosci 23(34):10756–10764PubMed
20.
go back to reference Sherer TB, Betarbet R, Greenamyre JT (2001) Pesticides and Parkinson’s disease. ScientificWorldJournal 1:207–208CrossRefPubMed Sherer TB, Betarbet R, Greenamyre JT (2001) Pesticides and Parkinson’s disease. ScientificWorldJournal 1:207–208CrossRefPubMed
21.
go back to reference Pan-Montojo F, Anichtchik O, Dening Y, Knels L, Pursche S, Jung R, Jackson S, Gille G, Spillantini MG, Reichmann H et al (2010) Progression of Parkinson’s disease pathology is reproduced by intragastric administration of rotenone in mice. PLoS One 5(1):e8762CrossRefPubMedPubMedCentral Pan-Montojo F, Anichtchik O, Dening Y, Knels L, Pursche S, Jung R, Jackson S, Gille G, Spillantini MG, Reichmann H et al (2010) Progression of Parkinson’s disease pathology is reproduced by intragastric administration of rotenone in mice. PLoS One 5(1):e8762CrossRefPubMedPubMedCentral
22.
go back to reference Maass A, Reichmann H (2013) Sleep and non-motor symptoms in Parkinson’s disease. J Neural Transm (Vienna) 120(4):565–569CrossRef Maass A, Reichmann H (2013) Sleep and non-motor symptoms in Parkinson’s disease. J Neural Transm (Vienna) 120(4):565–569CrossRef
23.
go back to reference Klingelhoefer L, Reichmann H (2015) Pathogenesis of Parkinson disease-the gut-brain axis and environmental factors. Nat Rev Neurol 11(11):625–636CrossRefPubMed Klingelhoefer L, Reichmann H (2015) Pathogenesis of Parkinson disease-the gut-brain axis and environmental factors. Nat Rev Neurol 11(11):625–636CrossRefPubMed
24.
go back to reference Aarsland D, Pahlhagen S, Ballard CG, Ehrt U, Svenningsson P (2012) Depression in Parkinson disease—epidemiology, mechanisms and management. Nat Rev Neurol 8(1):35–47CrossRef Aarsland D, Pahlhagen S, Ballard CG, Ehrt U, Svenningsson P (2012) Depression in Parkinson disease—epidemiology, mechanisms and management. Nat Rev Neurol 8(1):35–47CrossRef
25.
go back to reference Chen W, Xu ZM, Wang G, Chen SD (2012) Non-motor symptoms of Parkinson’s disease in China: a review of the literature. Parkinsonism Relat Disord 18(5):446–452CrossRefPubMed Chen W, Xu ZM, Wang G, Chen SD (2012) Non-motor symptoms of Parkinson’s disease in China: a review of the literature. Parkinsonism Relat Disord 18(5):446–452CrossRefPubMed
26.
go back to reference Pfeiffer RF (2012) Autonomic dysfunction in Parkinson’s disease. Expert Rev Neurother 12(6):697–706CrossRefPubMed Pfeiffer RF (2012) Autonomic dysfunction in Parkinson’s disease. Expert Rev Neurother 12(6):697–706CrossRefPubMed
27.
go back to reference Defazio G, Gigante A, Mancino P, Tinazzi M (2013) The epidemiology of pain in Parkinson’s disease. J Neural Transm (Vienna) 120(4):583–586CrossRef Defazio G, Gigante A, Mancino P, Tinazzi M (2013) The epidemiology of pain in Parkinson’s disease. J Neural Transm (Vienna) 120(4):583–586CrossRef
28.
go back to reference Todorova A, Jenner P, Ray Chaudhuri K (2014) Non-motor Parkinson’s: integral to motor Parkinson’s, yet often neglected. Pract Neurol 14(5):310–322CrossRefPubMedPubMedCentral Todorova A, Jenner P, Ray Chaudhuri K (2014) Non-motor Parkinson’s: integral to motor Parkinson’s, yet often neglected. Pract Neurol 14(5):310–322CrossRefPubMedPubMedCentral
29.
go back to reference Manning-Bog AB, McCormack AL, Li J, Uversky VN, Fink AL, Di Monte DA (2002) The herbicide paraquat causes up-regulation and aggregation of alpha-synuclein in mice: paraquat and alpha-synuclein. J Biol Chem 277(3):1641–1644CrossRefPubMed Manning-Bog AB, McCormack AL, Li J, Uversky VN, Fink AL, Di Monte DA (2002) The herbicide paraquat causes up-regulation and aggregation of alpha-synuclein in mice: paraquat and alpha-synuclein. J Biol Chem 277(3):1641–1644CrossRefPubMed
30.
go back to reference Manning-Bog AB, McCormack AL, Purisai MG, Bolin LM, Di Monte DA (2003) Alpha-synuclein overexpression protects against paraquat-induced neurodegeneration. J Neurosci 23(8):3095–3099PubMed Manning-Bog AB, McCormack AL, Purisai MG, Bolin LM, Di Monte DA (2003) Alpha-synuclein overexpression protects against paraquat-induced neurodegeneration. J Neurosci 23(8):3095–3099PubMed
31.
go back to reference Di Monte DA (2006) The environment and Parkinson’s disease: is the nigrostriatal system preferentially targeted by neurotoxins? Lancet Neurol 2(9):531–538CrossRef Di Monte DA (2006) The environment and Parkinson’s disease: is the nigrostriatal system preferentially targeted by neurotoxins? Lancet Neurol 2(9):531–538CrossRef
32.
go back to reference Gorell JM, Johnson CC, Rybicki BA, Peterson EL, Richardson RJ (1998) The risk of Parkinson’s disease with exposure to pesticides, farming, well water, and rural living. Neurology 50(5):1346–1350CrossRefPubMed Gorell JM, Johnson CC, Rybicki BA, Peterson EL, Richardson RJ (1998) The risk of Parkinson’s disease with exposure to pesticides, farming, well water, and rural living. Neurology 50(5):1346–1350CrossRefPubMed
33.
go back to reference Tanner CM, Kamel F, Ross GW, Hoppin JA, Goldman SM, Korell M, Marras C, Bhudhikanok GS, Kasten M, Chade AR et al (2011) Rotenone, paraquat, and Parkinson’s disease. Environ Health Perspect 119(6):866–872CrossRefPubMedPubMedCentral Tanner CM, Kamel F, Ross GW, Hoppin JA, Goldman SM, Korell M, Marras C, Bhudhikanok GS, Kasten M, Chade AR et al (2011) Rotenone, paraquat, and Parkinson’s disease. Environ Health Perspect 119(6):866–872CrossRefPubMedPubMedCentral
34.
go back to reference Holmqvist S, Chutna O, Bousset L, Aldrin-Kirk P, Li W, Bjorklund T, Wang ZY, Roybon L, Melki R, Li JY (2014) Direct evidence of Parkinson pathology spread from the gastrointestinal tract to the brain in rats. Acta Neuropathol 128(6):805–820CrossRefPubMed Holmqvist S, Chutna O, Bousset L, Aldrin-Kirk P, Li W, Bjorklund T, Wang ZY, Roybon L, Melki R, Li JY (2014) Direct evidence of Parkinson pathology spread from the gastrointestinal tract to the brain in rats. Acta Neuropathol 128(6):805–820CrossRefPubMed
35.
go back to reference Luk KC, Kehm V, Carroll J, Zhang B, O’Brien P, Trojanowski JQ, Lee VM (2012) Pathological alpha-synuclein transmission initiates Parkinson-like neurodegeneration in nontransgenic mice. Science 338(6109):949–953CrossRefPubMedPubMedCentral Luk KC, Kehm V, Carroll J, Zhang B, O’Brien P, Trojanowski JQ, Lee VM (2012) Pathological alpha-synuclein transmission initiates Parkinson-like neurodegeneration in nontransgenic mice. Science 338(6109):949–953CrossRefPubMedPubMedCentral
36.
go back to reference Desplats P, Lee HJ, Bae EJ, Patrick C, Rockenstein E, Crews L, Spencer B, Masliah E, Lee SJ (2009) Inclusion formation and neuronal cell death through neuron-to-neuron transmission of alpha-synuclein. Proc Natl Acad Sci USA 106(31):13010–13015CrossRefPubMedPubMedCentral Desplats P, Lee HJ, Bae EJ, Patrick C, Rockenstein E, Crews L, Spencer B, Masliah E, Lee SJ (2009) Inclusion formation and neuronal cell death through neuron-to-neuron transmission of alpha-synuclein. Proc Natl Acad Sci USA 106(31):13010–13015CrossRefPubMedPubMedCentral
37.
go back to reference Svensson E, Horvath-Puho E, Thomsen RW, Djurhuus JC, Pedersen L, Borghammer P, Sorensen HT (2015) Vagotomy and subsequent risk of Parkinson’s disease. Ann Neurol 78(4):522–529CrossRefPubMed Svensson E, Horvath-Puho E, Thomsen RW, Djurhuus JC, Pedersen L, Borghammer P, Sorensen HT (2015) Vagotomy and subsequent risk of Parkinson’s disease. Ann Neurol 78(4):522–529CrossRefPubMed
Metadata
Title
Changes in the sympathetic innervation of the gut in rotenone treated mice as possible early biomarker for Parkinson’s disease
Authors
Mike Arnhold
Yanina Dening
Michaël Chopin
Esteban Arévalo
Mathias Schwarz
Heinz Reichmann
Gabriele Gille
Richard H. W. Funk
Francisco Pan-Montojo
Publication date
01-06-2016
Publisher
Springer Berlin Heidelberg
Published in
Clinical Autonomic Research / Issue 3/2016
Print ISSN: 0959-9851
Electronic ISSN: 1619-1560
DOI
https://doi.org/10.1007/s10286-016-0358-6

Other articles of this Issue 3/2016

Clinical Autonomic Research 3/2016 Go to the issue