Enteric nervous system α-synuclein immunoreactivity in idiopathic REM sleep behavior disorder

Fabienne S Sprenger¹, Nadia Stefanova¹, Ellen Gelpi¹, Klaus Seppi¹, Judith Navarro-Otano¹, Felix Offner¹, Dolores Vilas¹, Francesc Valldeoriola¹, Claustre Pont-Sunyer¹, Iban Aldecoa¹, Carles Gaig¹, Angels Gines¹, Miriam Cuatrecasas¹, Birgit Högl¹, Birgit Frauscher¹, Alex Iranzo¹, Gregor K Wenning¹, Wolfgang Vogel¹, Eduardo Tolosa¹, Werner Poewe²

Affiliations

¹ From the Departments of Neurology (F.S.S., N.S., K.S., B.H., B.F., G.K.W., W.P.) and Gastroenterology (W.V.), Medical University of Innsbruck, Austria; Neurological Tissue Bank of the Biobanc-Hospital Clinic de Barcelona (E.G.), IDIBAPS; the Departments of Neurology (J.N.-O., D.V., F.V., C.P.-S., C.G., A.I., E.T.), Pathology (I.A., M.C.), and Gastroenterology (A.G.), Hospital Clinic de Barcelona, Spain; and the Institute of Pathology (F.O.), Academic Teaching Hospital, Feldkirch, Austria.
² From the Departments of Neurology (F.S.S., N.S., K.S., B.H., B.F., G.K.W., W.P.) and Gastroenterology (W.V.), Medical University of Innsbruck, Austria; Neurological Tissue Bank of the Biobanc-Hospital Clinic de Barcelona (E.G.), IDIBAPS; the Departments of Neurology (J.N.-O., D.V., F.V., C.P.-S., C.G., A.I., E.T.), Pathology (I.A., M.C.), and Gastroenterology (A.G.), Hospital Clinic de Barcelona, Spain; and the Institute of Pathology (F.O.), Academic Teaching Hospital, Feldkirch, Austria. Werner.Poewe@i-med.ac.at.

PMID: 26475692
PMCID: PMC4653104
DOI: 10.1212/WNL.0000000000002126

Enteric nervous system α-synuclein immunoreactivity in idiopathic REM sleep behavior disorder

Fabienne S Sprenger et al. Neurology. 2015.

. 2015 Nov 17;85(20):1761-8.

doi: 10.1212/WNL.0000000000002126. Epub 2015 Oct 16.

Authors

Affiliations

¹ From the Departments of Neurology (F.S.S., N.S., K.S., B.H., B.F., G.K.W., W.P.) and Gastroenterology (W.V.), Medical University of Innsbruck, Austria; Neurological Tissue Bank of the Biobanc-Hospital Clinic de Barcelona (E.G.), IDIBAPS; the Departments of Neurology (J.N.-O., D.V., F.V., C.P.-S., C.G., A.I., E.T.), Pathology (I.A., M.C.), and Gastroenterology (A.G.), Hospital Clinic de Barcelona, Spain; and the Institute of Pathology (F.O.), Academic Teaching Hospital, Feldkirch, Austria.
² From the Departments of Neurology (F.S.S., N.S., K.S., B.H., B.F., G.K.W., W.P.) and Gastroenterology (W.V.), Medical University of Innsbruck, Austria; Neurological Tissue Bank of the Biobanc-Hospital Clinic de Barcelona (E.G.), IDIBAPS; the Departments of Neurology (J.N.-O., D.V., F.V., C.P.-S., C.G., A.I., E.T.), Pathology (I.A., M.C.), and Gastroenterology (A.G.), Hospital Clinic de Barcelona, Spain; and the Institute of Pathology (F.O.), Academic Teaching Hospital, Feldkirch, Austria. Werner.Poewe@i-med.ac.at.

PMID: 26475692
PMCID: PMC4653104
DOI: 10.1212/WNL.0000000000002126

Abstract

Objective: To investigate the expression of α-synuclein in colonic biopsies of patients with idiopathic REM sleep behavior disorder (iRBD) and address if α-synuclein immunostaining of tissue obtained via colonic biopsies holds promise as a diagnostic biomarker for prodromal Parkinson disease (PD).

Methods: Patients with iRBD, patients with PD, and healthy controls were prospectively recruited to undergo colonic biopsies for comparison of α-synuclein immunoreactivity patterns between the groups by using 2 different antibodies.

Results: There was no difference in colonic mucosal and submucosal immunostaining between groups using the 15G7 α-synuclein antibody, which was found in almost all participants enrolled in this study. By contrast, immunostaining for serine 129-phosphorylated α-synuclein (pSyn) in submucosal nerve fibers or ganglia was found in none of 14 controls but was observed in 4 of 17 participants with iRBD and 1 out of 19 patients with PD.

Conclusions: The present findings of pSyn immunostaining of colonic biopsies in a substantial proportion of iRBD participants raise the possibility that this tissue marker may be a suitable candidate to study further as a prodromal PD marker in at-risk cohorts.

PubMed Disclaimer

Figures

**Figure 1. Patterns of 15G7 α-synuclein immunostaining in colonic biopsies**
Total α-synuclein expression in colonic biopsies detected with the 15G7 antibody. (A) α-Synuclein-positive nerve fibers (arrows) were identified in lamina propria of the mucosa. (B) α-Synuclein expression was detected with the 15G7 antibody in mucosal macrophages (arrows) in the lamina propria at the border to muscularis mucosae. (C) Immunopositive nerve fibers (arrows) were also commonly seen in muscularis mucosae. (D) α-Synuclein-positive nerve fibers (arrows) were detected in the submucosa of colonic biopsies. Submucosal ganglionic nerve cells showed variable pattern of α-synuclein immunostaining in the cytoplasm: (E) diffuse; (F) distinct punctate (arrows); or (G) coarse aggregate-like (arrows). Scale bars, 20 μm.

**Figure 2. α-Synuclein expression in submucosal ganglionic nerve cells of colonic biopsies**
Submucosal ganglionic nerve cells coexpress the neuronal marker HuC/HuD (red, A, D) and α-Synuclein identified by 15G7 antibody (green, B, E), as proven by the merge of the labeling in C and F, with blue representing DAPI nuclear counterstaining. Scale bars, 20 μm.

**Figure 3. pSyn submucosal immunostaining patterns in colonic biopsy material**
Phosphorylated α-synuclein (pSyn) submucosal staining patterns in colonic biopsies. (A) pSyn-immunopositive nerve fiber in the submucosa (arrows). (B) pSyn-positive aggregates in the cytoplasm of submucosal ganglionic nerve cells (arrows). (C) Diffuse pSyn cytoplasmic immunoreactivity in submucosal ganglia (arrows). Scale bars, 20 μm.

See this image and copyright information in PMC

Comment in

Does REM sleep behavior disorder have the guts to be Parkinson disease?
Unger MM, Sakakibara R. Unger MM, et al. Neurology. 2015 Nov 17;85(20):1732-3. doi: 10.1212/WNL.0000000000002130. Epub 2015 Oct 16. Neurology. 2015. PMID: 26475696 No abstract available.

References

1. den HJW, Bethlem J. The distribution of Lewy bodies in the central and autonomic nervous systems in idiopathic paralysis agitans. J Neurol Neurosurg Psychiatry 1960;23:283–290. - PMC - PubMed
1. Braak H, de Vos RA, Bohl J, Del Tredici K. Gastric alpha-synuclein immunoreactive inclusions in Meissner's and Auerbach's plexuses in cases staged for Parkinson's disease-related brain pathology. Neurosci Lett 2006;396:67–72. - PubMed
1. Beach TG, Adler CH, Sue LI, et al. Multi-organ distribution of phosphorylated alpha-synuclein histopathology in subjects with Lewy body disorders. Acta Neuropathol 2010;119:689–702. - PMC - PubMed
1. Pouclet H, Lebouvier T, Coron E, et al. A comparison between rectal and colonic biopsies to detect Lewy pathology in Parkinson's disease. Neurobiol Dis 2012;45:305–309. - PubMed
1. Lebouvier T, Neunlist M, Bruley des Varannes S, et al. Colonic biopsies to assess the neuropathology of Parkinson's disease and its relationship with symptoms. PLoS One 2010;5:e12728. - PMC - PubMed

Publication types

Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Enteric nervous system α-synuclein immunoreactivity in idiopathic REM sleep behavior disorder

Affiliations

Enteric nervous system α-synuclein immunoreactivity in idiopathic REM sleep behavior disorder

Authors

Affiliations

Abstract

Figures

Comment in

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Molecular Biology Databases