Direct evidence of Parkinson pathology spread from the gastrointestinal tract to the brain in rats

The cellular hallmarks of Parkinson's disease (PD) are the loss of nigral dopaminergic neurons and the formation of alpha-synuclein-enriched Lewy bodies and Lewy neurites in the remaining neurons. Based on the topographic distribution of Lewy bodies established after autopsy of brains from PD patients, Braak and coworkers hypothesized that Lewy pathology primes in the enteric nervous system and spreads to the brain, suggesting an active retrograde transport of alpha-synuclein (the key protein component in Lewy bodies), via the vagal nerve. This hypothesis, however, has not been tested experimentally thus far. Here, we use a human PD brain lysate containing different forms of alpha-synuclein (monomeric, oligomeric and fibrillar), and recombinant alpha-synuclein in an in vivo animal model to test this hypothesis. We demonstrate that alpha-synuclein present in the human PD brain lysate and distinct recombinant alpha-synuclein forms are transported via the vagal nerve and reach the dorsal motor nucleus of the vagus in the brainstem in a time-dependent manner after injection into the intestinal wall. Using live cell imaging in a differentiated neuroblastoma cell line, we determine that both slow and fast components of axonal transport are involved in the transport of aggregated alpha-synuclein. In conclusion, we here provide the first experimental evidence that different alpha-synuclein forms can propagate from the gut to the brain, and that microtubule-associated transport is involved in the translocation of aggregated alpha-synuclein in neurons.