Alpha-Synuclein in the Appendiceal Mucosa of Neurologically Intact Subjects

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 alpha-synuclein aggregation with subsequent spread to the central nervous system. Regional variations in the spatial pattern or levels of alpha-synuclein along the enteric nervous system could have implications for identifying sites of onset of this pathogenic cascade. We performed immunohistochemical staining for alpha-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 alpha-synuclein-containing axonal varicosities, concentrated in its mucosal plexus rather than the classical submucosal and myenteric plexuses. Unexpectedly, intralysosomal accumulations of alpha-synuclein were detected within mucosal macrophages of the appendix. The abundance and accumulation of alpha-synuclein in the vermiform appendix implicate it as a candidate anatomical locus for the initiation of enteric alpha-synuclein aggregation and permits the generation of testable hypotheses for Parkinson's disease pathogenesis. (C) 2013 International Parkinson and Movement Disorder Society