Accumulation of Alpha-synuclein Causes Colonic Dysmotility Independently of Enteric Nervous Damage in the Early Stage of Parkinson's Disease (Neurogastroenterol Motil 2012;24:e425-e436)

Abstract

Parkinson's disease (PD) is a chronic, progressive neurodegenerative disorder, which is characterized by severe movement impairment.1 The main pathologic feature of PD is a damage of the nigrostriatal dopaminergic pathway and the presence of cyto-plasmic protein aggregates, known as Lewy bodies (LB), in remaining dopaminergic cells.1,2 However, pathology of PD was observed in other area including gastrointestinal (GI) tract and constipation is the most common non-motor symptom of PD.1 Only a few studies have reported the alteration of enteric nervous system (ENS) related to GI dysfunction in PD.2,3 Wang et al4 recently reported age-related alterations in colonic myenteric ganglia and defecation using mice overexpressing wild-type human α-synuclein under the Thy-1 promoter (Thy1-aSyn). They previously reported that 12 months old mice overexpressing α-synuclein exhibited increased colonic transit time and content compared with wild-type.5 In current experiment, they investigated whether the onset of colonic motor dysfunction in Thy1-aSyn mice occurred at earlier lifetime. When mice were exposed to novel environment which consisted of placing singly in a new cage without food, Thy1-aSyn mice aged 2.5-3 and 7-8 months exhibited decreased fecal pellet expulsion at 15 min compared to control. While 2.5-3 months old mice did not show significant reduction in the 30-60 minutes, 7-8 months old mice had continuous reduction during 15-60 minutes. These mice subsequently were re-fed during 2 hours and showed significantly decreased fecal pellet output compared to controls in both age. Interestingly, there was no significant change in gastric emptying in Thy1-aSyn mice. Colonic tyrosine hydroxylase, vasoactive intestinal polypeptide (VIP), peripheral choline acetyltransferase (pChAT) and neuronal nitric oxide synthase (nNOS) immunoreactivity were not significantly different between Thy1-aSyn mice and control. However, the staining for α-synuclein was 3-fold higher in Thy1-aSyn mice compared to control and it was mainly localized to varicosities adjacent to pChAT immunoreactive neuronal fibers. Authors concluded that α-synuclein is overproduced in the ENS earlier than the loss of striatal dopamine, and enteric neurotransmitters such as dopamine, VIP and nitric oxide may not be important in the colon dysmotility at least in the early stage of PD.