Mice Overexpressing Wild-Type Human Alpha-Synuclein Display Alterations in Colonic Myenteric Ganglia and Defecation

Neurogastroenterol Motil. 2012 Sep;24(9):e425-36. doi: 10.1111/j.1365-2982.2012.01974.x. Epub 2012 Jul 11.

Abstract

Background: Prevalent non-motor symptoms of Parkinson's disease (PD) include gastrointestinal motor impairments and advanced stage PD displays pathological aggregates of α-synuclein in colonic enteric neurons. We previously showed that 12 months old mice overexpressing human wild type (WT) α-synuclein under the Thy1 promoter (Thy1-aSyn) displayed colonic motor dysfunction. We investigated functional gut alterations at earlier ages and histological correlates.

Methods: Defecation, gastric emptying (GE), and immunostaining for α-synuclein, peripheral choline acetyltransferase (pChAT), tyrosine hydroxylase (TH), neuronal nitric oxide synthase (nNOS), and vasoactive intestinal peptide (VIP) in distal colon myenteric plexuses were assessed in male Thy1-aSyn compared to littermate WT mice.

Key results: Thy1-aSyn mice aged 2.5-3 or 7-8 months old had 81% and 55% reduction in fecal pellet output, respectively, in the first 15 min of exposure to a novel environment. The reduction remained significant in the older group for 2-h, and subsequent refeeding resulted also in a 60% and 69% reduction of defecation in the first hour, respectively. Thy1-aSyn mice (8-10 months) displayed increased α-synuclein in the myenteric plexuses with abundant varicose terminals surrounding pChAT-immunoreactive (ir) neurons, and only a few, nNOS-ir neurons. There were no conspicuous changes in pChAT- and nNOS-ir neurons, or TH- and VIP-ir nerve fibers. Thy1-aSyn mice aged 4-18 months had normal GE.

Conclusions & inferences: The occurrence of over-production of pre-synaptic α-synuclein in colonic myenteric ganglia several months before the loss of striatal dopamine may provide an anatomical basis for interference with cholinergic neuronal activation, causing an early impairment in defecation to stimuli.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Choline O-Acetyltransferase / metabolism
  • Colon / innervation
  • Colon / physiology*
  • Colon / physiopathology
  • Defecation / physiology*
  • Ganglia, Autonomic / metabolism*
  • Ganglia, Autonomic / physiopathology
  • Gastric Emptying / physiology
  • Male
  • Mice
  • Mice, Transgenic
  • Myenteric Plexus / metabolism*
  • Myenteric Plexus / physiopathology
  • Neurons / metabolism
  • Nitric Oxide Synthase Type I / metabolism
  • Parkinson Disease / metabolism
  • Parkinson Disease / physiopathology
  • Tyrosine 3-Monooxygenase / metabolism
  • alpha-Synuclein / metabolism*

Substances

  • alpha-Synuclein
  • Nitric Oxide Synthase Type I
  • Nos1 protein, mouse
  • Tyrosine 3-Monooxygenase
  • Choline O-Acetyltransferase