title: 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.
authors.affiliation: Centre for Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada; Department of Pathology and Laboratory Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada; Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Madison T
authors.initials: MT
authors.lastname: Gray
authors.forename: David G
authors.initials: DG
authors.lastname: Munoz
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Gray
authors.forename: Michael G
authors.initials: MG
authors.lastname: Schlossmacher
authors.forename: John M
authors.initials: JM
authors.lastname: Woulfe
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015703:Antigens, CD / Q000378:metabolism; D018952:Antigens, CD34 / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D005753:Gastric Mucosa / Q000378:metabolism*; D041981:Gastrointestinal Tract / Q000378:metabolism*; D006801:Humans; D008264:Macrophages / Q000378:metabolism; D008875:Middle Aged; D009412:Nerve Fibers / Q000378:metabolism; D016708:Synaptophysin / Q000378:metabolism; D043222:Ubiquitin Thiolesterase / Q000378:metabolism; D014660:Vasoactive Intestinal Peptide / Q000378:metabolism; D051844:alpha-Synuclein / Q000032:analysis* / Q000378:metabolism*; D000097382:CD68 Molecule
chemical_list: D015703:Antigens, CD; D018952:Antigens, CD34; D015214:Antigens, Differentiation, Myelomonocytic; D016708:Synaptophysin; D043222:Ubiquitin Thiolesterase; D014660:Vasoactive Intestinal Peptide; D051844:alpha-Synuclein; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C569014:SYP protein, human; C482860:UCHL1 protein, human
keywords: Parkinson's disease; enteric nervous system; mucosal plexus; vermiform appendix; α-synuclein