Alimentary, my dear Watson? The challenges of enteric α‐synuclein as a Parkinson's disease biomarker

Abstract

An accurate early diagnostic test for Parkinson's disease (PD) is a critical unmet need. Recently, independent groups using different histological techniques have reported that the presence of alpha-synuclein (α-syn) in colonic biopsy tissue is able to distinguish living patients with PD from those without the disease. In addition, a further study has suggested that the presence of α-syn in colonic biopsy tissue may be evident in early or even prodromal PD. However, several questions remain regarding the translation of these findings into using the assessment of α-syn deposition in the enteric nervous system as a diagnostic biomarker for prodromal PD. Here we address critical issues related to the location and quantification of enteric α-syn, detection of α-syn with currently available histological techniques, timing of detection of α-syn deposition, and, most crucially, whether enteric α-syn can distinguish those with PD from both healthy individuals and individuals with other related diseases. We conclude that, although enteric α-syn is a very exciting prospect, further studies will be vital to determine whether enteric α-syn deposition has the potential to be the biomarker for prodromal PD that the field so desperately seeks.

Alpha-synuclein immunoreactivity patterns in the enteric nervous system

“…We believe that the study reported here is a step in this direction. Harmonization of the terminology used to describe different reactivity patterns and their biological interpretation (physiological vs pathological) would be also needed, as has been recently discussed [18,25].…”

Colonic mucosal α-synuclein lacks specificity as a biomarker for Parkinson disease

“…4 Several recent studies of aSyn staining in colonic tissue from living patients with PD report sensitivities ranging from 72% to a remarkable 100%. [5][6][7] However, the description of some degree of aSyn labeling in controls in these studies and reports of aSyn in colonic tissue from individuals without PD have raised concerns regarding specificity. 8,9 The aim of the present study was to optimize the immunohistochemical detection of aSyn in colonic biopsies by adapting the paraffin-embedded tissue (PET) blot, a method developed to increase sensitivity and specificity of detecting aggregated proteins in a related proteinopathy, Creutzfeldt-Jakob disease.…”

“…As we and others have recently discussed, a key issue in using aSyn as a peripheral tissue PD biomarker concerns what signal is to be considered "pathologic" and what is "normal." 5,21 Many studies reporting lack of colonic aSyn staining in healthy individuals nevertheless note some degree of positivity that is labeled "normal" or "nonspecific." 6,7,22 Our study, along with other studies, would suggest that Ser129p-aSyn in healthy colon is not necessarily pathologic.…”

“…As we and others have discussed, sensitivity and specificity are clearly influenced by details of sampling technique, such as the number of sections, section thickness, number of slides analyzed, and amount of tissue available. 5,7,22,23 Future efforts involving sharing of tissues and methodologies will be critical in determining the potential of colonic aSyn as a PD biomarker.…”

Unmet needs in Parkinson's disease: New horizons in a changing landscape

“…Several potential biomarkers have been pursued, ranging from neuroimaging to possible markers in the blood [19], CSF [20], and even the colon [21]. Specifically, molecular pathways related to a-synuclein, tau and b-amyloid peptides have received considerable attention.…”