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 α-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 α-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 α-synuclein
(monomeric, oligomeric and fibrillar), and recombinant α-synuclein in an
in vivo animal model to test this hypothesis. We demonstrate that
α-synuclein present in the human PD brain lysate and distinct
recombinant α-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 α-synuclein. In conclusion, we
here provide the first experimental evidence that different α-synuclein
forms can propagate from the gut to the brain, and that
microtubule-associated transport is involved in the translocation of
aggregated α-synuclein in neurons.