Age-dependent alpha-synuclein accumulation and aggregation in the colon of a transgenic mouse model of Parkinson's disease

Background: Parkinson's disease (PD) is one of the most common neurodegenerative diseases, neuropathologically characterized by misfolded protein aggregation, called Lewy bodies and Lewy neurites. PD is a slow-progressive disease with colonic dysfunction appearing in the prodromal stage and lasting throughout the course of the disease. Methods: In order to study PD pathology in the colon, we examined the age-dependent morphological and pathological changes in the colon of a PD mouse model expressing human wildtype alpha-synuclein (alpha-syn) fused with the green fluorescent protein (GFP), under the endogenous mouse alpha-syn promoter. Results: We observed an age-dependent progressive expression and accumulation of alpha-syn-GFP in the enteric neurons of Meissner's (submucosal) and Auerbach's (myenteric) plexuses of the colon. Additionally, the phosphorylation of alpha-syn at serine 129 also increased with age and the aggregation of alpha-syn-GFP coincided with the appearance of motor deficits at 9 months of age. Furthermore, alpha-syn (-GFP) distinctly co-localized with different subtypes of neurons, as identified by immunohistochemical labeling of vasoactive intestinal peptide (VIP), neuronal nitric oxide synthase (nNOS), and calretinin. Conclusions: Our results show the development of alpha-syn pathology in the enteric neurons of the colon in a PD mouse model, which coincide with the appearance of motor deficits. Our mouse model possesses the potential and uniqueness for studying PD gastrointestinal dysfunction.