Examination of Abnormal Alpha-synuclein Aggregates in the Enteric Neural Plexus in Patients with Ulcerative Colitis

Background & Aims: Parkinson's disease (PD) is the second most neurodegenerative disease after Alzheimer's disease. Accumulating knowledge points to the notion that abnormal aggregation of alpha-synuclein (alpha Syn) starts in the gut and ascends to the substantia nigra via the vagus nerve in about a half of PD patients. Epidemiological studies revealed that ulcerative colitis (UC) increased the a risk for PD 1.3 to 1.8-folds. However, it remains unknown whether alpha Syn is abnormally aggregated in the enteric neurons in UC patients. Methods: We first inspected and optimized the immunostaining protocols with an anti-phosphorylated alpha Syn antibody, pSyn#64, using the brain and the gut of eight autopsied cases (five with PD and three without PD). Then, we examined abnormal alpha Syn aggregation in the enteric neurons in 23 and 18 colectomized patients with and without UC, respectively. Five or more sections were stained for alpha Syn in each of 87 and 25 paraffinembedded blocks in patients with and without UC, respectively. Results: Ten different protocols of epitope exposure appropriately stained aggregated alpha Syn in the brain, but only a complete lack of epitope exposure stained aggregated alpha Syn in the colon with low background. Abnormal alpha Syn aggregates, which was confirmed by co-localization of p62, in the enteric neurons were detected in a single patient with UC but in no patient without UC. Conclusions: Omission of epitope exposure enabled us to immunostain aggregated alpha Syn in the colon by pSyn#64 with low nonspecific staining, but the number of 23 UC patients was not high enough to discern whether abnormal alpha Syn aggregation in the colonic neural plexus was increased in UC or not.