PMID- 22779732 OWN - NLM STAT- MEDLINE DCOM- 20130208 LR - 20211021 IS - 1365-2982 (Electronic) IS - 1350-1925 (Print) IS - 1350-1925 (Linking) VI - 24 IP - 9 DP - 2012 Sep TI - Mice overexpressing wild-type human alpha-synuclein display alterations in colonic myenteric ganglia and defecation. PG - e425-36 LID - 10.1111/j.1365-2982.2012.01974.x [doi] AB - BACKGROUND: Prevalent non-motor symptoms of Parkinson's disease (PD) include gastrointestinal motor impairments and advanced stage PD displays pathological aggregates of alpha-synuclein in colonic enteric neurons. We previously showed that 12 months old mice overexpressing human wild type (WT) alpha-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 alpha-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 alpha-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 alpha-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. CI - (c) 2012 Blackwell Publishing Ltd. FAU - Wang, L AU - Wang L AD - CURE: Digestive Diseases Research Center and Center for Neurobiology of Stress, Department of Medicine, Division of Digestive Diseases, David Geffen School of Medicine, University of California Los Angeles and Veteran Affairs Greater Los Angeles Healthcare System, Los Angeles, USA. lixinw@ucla.edu FAU - Magen, I AU - Magen I FAU - Yuan, P-Q AU - Yuan PQ FAU - Subramaniam, S R AU - Subramaniam SR FAU - Richter, F AU - Richter F FAU - Chesselet, M-F AU - Chesselet MF FAU - Tache, Y AU - Tache Y LA - eng GR - P30 DK041301/DK/NIDDK NIH HHS/United States GR - P50 NS038367/NS/NINDS NIH HHS/United States GR - R01 DK057238/DK/NIDDK NIH HHS/United States GR - R01 DK 57238/DK/NIDDK NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20120711 PL - England TA - Neurogastroenterol Motil JT - Neurogastroenterology and motility JID - 9432572 RN - 0 (alpha-Synuclein) RN - EC 1.14.13.39 (Nitric Oxide Synthase Type I) RN - EC 1.14.13.39 (Nos1 protein, mouse) RN - EC 1.14.16.2 (Tyrosine 3-Monooxygenase) RN - EC 2.3.1.6 (Choline O-Acetyltransferase) SB - IM MH - Animals MH - Choline O-Acetyltransferase/metabolism MH - Colon/innervation/*physiology/physiopathology MH - Defecation/*physiology MH - Ganglia, Autonomic/*metabolism/physiopathology MH - Gastric Emptying/physiology MH - Male MH - Mice MH - Mice, Transgenic MH - Myenteric Plexus/*metabolism/physiopathology MH - Neurons/metabolism MH - Nitric Oxide Synthase Type I/metabolism MH - Parkinson Disease/metabolism/physiopathology MH - Tyrosine 3-Monooxygenase/metabolism MH - alpha-Synuclein/*metabolism PMC - PMC3712640 MID - NIHMS477572 EDAT- 2012/07/12 06:00 MHDA- 2013/02/09 06:00 PMCR- 2013/09/01 CRDT- 2012/07/12 06:00 PHST- 2012/07/12 06:00 [entrez] PHST- 2012/07/12 06:00 [pubmed] PHST- 2013/02/09 06:00 [medline] PHST- 2013/09/01 00:00 [pmc-release] AID - 10.1111/j.1365-2982.2012.01974.x [doi] PST - ppublish SO - Neurogastroenterol Motil. 2012 Sep;24(9):e425-36. doi: 10.1111/j.1365-2982.2012.01974.x. Epub 2012 Jul 11.