Brain-to-gut trafficking of alpha-synuclein by CD11c⁺ cells in a mouse model of Parkinson's disease

Inflammation in the brain and gut is a critical component of several neurological diseases, such as Parkinson's disease (PD). One trigger of the immune system in PD is aggregation of the pre-synaptic protein, alpha-synuclein (alpha Syn). Understanding the mechanism of propagation of alpha Syn aggregates is essential to developing disease-modifying therapeutics. Using a brain-first mouse model of PD, we demonstrate alpha Syn trafficking from the brain to the ileum of male mice. Immunohistochemistry revealed that the ileal alpha Syn aggregations are contained within CD11c+ cells. Using single-cell RNA sequencing, we demonstrate that ileal CD11c+ cells are microglia-like and the same subtype of cells is activated in the brain and ileum of PD mice. Moreover, by utilizing mice expressing the photo-convertible protein, Dendra2, we show that CD11c+ cells traffic from the brain to the ileum. Together these data provide a mechanism of alpha Syn trafficking between the brain and gut.