Alpha-synuclein in the appendiceal mucosa of neurologically intact subjects

Mov Disord. 2014 Jul;29(8):991-8. doi: 10.1002/mds.25779. Epub 2013 Dec 18.

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.

Keywords: Parkinson's disease; enteric nervous system; mucosal plexus; vermiform appendix; α-synuclein.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antigens, CD / metabolism
  • Antigens, CD34 / metabolism
  • Antigens, Differentiation, Myelomonocytic / metabolism
  • Gastric Mucosa / metabolism*
  • Gastrointestinal Tract / metabolism*
  • Humans
  • Macrophages / metabolism
  • Middle Aged
  • Nerve Fibers / metabolism
  • Synaptophysin / metabolism
  • Ubiquitin Thiolesterase / metabolism
  • Vasoactive Intestinal Peptide / metabolism
  • alpha-Synuclein / analysis*
  • alpha-Synuclein / metabolism*

Substances

  • Antigens, CD
  • Antigens, CD34
  • Antigens, Differentiation, Myelomonocytic
  • CD68 antigen, human
  • SYP protein, human
  • Synaptophysin
  • UCHL1 protein, human
  • alpha-Synuclein
  • Vasoactive Intestinal Peptide
  • Ubiquitin Thiolesterase