Preclinical Detection of Alpha-Synuclein Seeding Activity in the Colon of a Transgenic Mouse Model of Synucleinopathy by RT-QuIC

Abstract

In synucleinopathies such as Parkinson's disease (PD) and dementia with Lewy body (DLB), pathological alpha-synuclein (alpha-syn) aggregates are found in the gastrointestinal (GI) tract as well as in the brain. In this study, using real-time quaking-induced conversion (RT-QuIC), we investigated the presence of alpha-syn seeding activity in the brain and colon tissue of G2-3 transgenic mice expressing human A53T alpha-syn. Here we show that pathological alpha-syn aggregates with seeding activity were present in the colon of G2-3 mice as early as 3 months old, which is in the presymptomatic stage prior to the observation of any neurological abnormalities. In contrast, alpha-syn seeding activity was not detectable in 3 month-old mouse brains and only identified at 6 months of age in one of three mice. In the symptomatic stage of 12 months of age, RT-QuIC seeding activity was consistently detectable in both the brain and colon of G2-3 mice. Our results indicate that the RT-QuIC assay can presymptomatically detect pathological alpha-syn aggregates in the colon of G2-3 mice several months prior to their detection in brain tissue.