Transmission of Synucleinopathies in the Enteric Nervous System of A53T Alpha-Synuclein Transgenic Mice

ABSTRACT

Parkinson's disease (PD) and dementia with Lewy bodies (DLB) are characterized by abnormal deposition of alpha-synuclein aggregates in many regions of the central and peripheral nervous systems. Accumulating evidence suggests that the alpha-synuclein pathology initiates in a few discrete regions and spreads to larger areas in the nervous system. Recent pathological studies of PD patients have raised the possibility that the enteric nervous system is one of the initial sites of alpha-synuclein aggregation and propagation. Here, we evaluated the induction and propagation of alpha-synuclein aggregates in the enteric nervous system of the A53T alpha-synuclein transgenic mice after injection of human brain tissue extracts into the gastric walls of the mice. Western analysis of the brain extracts showed that the DLB extract contained detergent-stable alpha-synuclein aggregates, but the normal brain extract did not. Injection of the DLB extract resulted in an increased deposition of alpha-synuclein in the myenteric neurons, in which alpha-synuclein formed punctate aggregates over time up to 4 months. In these mice, inflammatory responses were increased transiently at early time points. None of these changes were observed in the A53T mice injected with saline or the normal brain extract, nor were these found in the wild type mice injected with the DLB extract. These results demonstrate that pathological alpha-synuclein aggregates present in the brain of DLB patient can induce the aggregation of endogenous alpha-synuclein in the myenteric neurons in A53T mice, suggesting the transmission of synucleinopathy lesions in the enteric nervous system.