Alpha‐synuclein in the appendiceal mucosa of neurologically intact subjects

Abstract

Parkinson's disease is characterized by the pathological aggregation of Alpha-synuclein. The dual-hit hypothesis proposed by Braak implicates the enteric nervous system as an initial site of α-synuclein aggregation with subsequent spread to the central nervous system. Regional variations in the spatial pattern or levels of α-synuclein along the enteric nervous system could have implications for identifying sites of onset of this pathogenic cascade. We performed immunohistochemical staining for α-synuclein on gastrointestinal tissue from patients with no history of neurological disease using the established LB509 antibody and a new clone, MJFR1, characterized for immunohistochemistry here. We demonstrate that the vermiform appendix is particularly enriched in α-synuclein-containing axonal varicosities, concentrated in its mucosal plexus rather than the classical submucosal and myenteric plexuses. Unexpectedly, intralysosomal accumulations of α-synuclein were detected within mucosal macrophages of the appendix. The abundance and accumulation of α-synuclein in the vermiform appendix implicate it as a candidate anatomical locus for the initiation of enteric α-synuclein aggregation and permits the generation of testable hypotheses for Parkinson's disease pathogenesis.

Neuronal Protein Alteration in Enteric Dysmotility Syndrome

“…Our observations are in line with Gray and colleagues, indicating that all neurologically intact subjects display αS-IR in their ganglion cell population [12]. Previous reports have reported αS-IR in none or in 8% to 82% of the neurologically intact subjects [11][12][13][14][15]. This discrepancy is related to the different antibodies used, different material assessed, i.e., surgical vs. post-mortem samples and the type of the sample, i.e., full thickness surgical sample vs. superficial endoscopic biopsy.…”

“…Physiological 42/αS-IR was observed in the lamina propria, the submucosa, and particularly in the numerous ganglion cells of the myenteric plexus. Our observations are in line with Gray and colleagues, indicating that all neurologically intact subjects display αS-IR in their ganglion cell population [12]. Previous reports have reported αS-IR in none or in 8% to 82% of the neurologically intact subjects [11][12][13][14][15].…”

“…It has been reported that in PD, αS-IR is seen not only in the brain but also in the visceral organs; moreover, in 2014, Gray and colleagues reported that αS IR was also seen in the neurologically intact subjects [3,12].…”

Detection of alpha‐synuclein conformational variants from gastro‐intestinal biopsy tissue as a potential biomarker for Parkinson's disease

“…We found several cases with staining of epithelial cells of gastric glands that was considered to be a nondisease‐related cross‐reaction to some secretory protein or enzymes of the gastric mucosa 33. Cellular elements detected, on the other hand, could represent mucosal macrophages ingesting pathological aSyn but their role in PD pathogenesis remains to be established 18. Therefore, the detection of non‐neuronal aSyn does not necessarily indicate a disease state.…”

“…It has, however, become increasingly apparent that the high sensitivity and specificity of GI aSyn detection to identify PD patients reported in the earlier studies 12, 13, 14, 15, 16 has not been sustained in subsequent studies repeatedly detecting aSyn accumulation also in the GI tract of neurologically healthy individuals 17, 18, 19, 20, 21. This was also confirmed by a recent multicentre study, which showed limited diagnostic value for detecting aSyn deposition in the GI biopsies by immunohistochemistry (IHC) 22.…”