Synuclein travels gut to brain in rats

The research record

This is the project's file for this landmark, as written and checked. Sources are listed at the end; anything not yet confirmed is marked "Not yet verified".

Who

Sara Holmqvist, Jia-Yi Li (last author), Ronald Melki, Luc Bousset, Laurent Roybon, Tomas Björklund, Oldriska Chutna, Patrick Aldrin-Kirk and colleagues (Acta Neuropathol 128:805–820, 2014). Funders were not checked.

What happened

Braak's staging (landmark 6) proposed that Lewy pathology starts in the gut's nerves and climbs to the brain via the vagus nerve. The team injected into the intestinal wall of rats either a lysate (a ground-up extract) of human Parkinson's brain containing several forms of synuclein, or recombinant (lab-made) synuclein as monomers, oligomers or fibrils (see landmark 43 for fibril models).

• Synuclein was carried along the vagus nerve and reached the dorsal motor nucleus of the vagus, a brainstem area, in a time-dependent way.
• Live imaging in a nerve-cell line showed both slow and fast axonal transport (the cell's internal delivery system) carry aggregated synuclein.

The abstract calls it the first experimental evidence that different synuclein forms can propagate from gut to brain.

Why it moved us toward a cure

It showed that a physical route exists, which makes the idea of blocking early spread plausible. Later mouse work found fibrils in the gut reaching the brain and causing damage (landmark 18). Human registry studies tried the same question (landmark 83).

Outcome

Open. This shows that synuclein can travel, not that Parkinson's in people starts this way or that the rats developed disease. No therapy follows from it yet. A 2020 baboon study, which injected Parkinson's Lewy body extracts into the gut, found nigrostriatal lesions but no synuclein lesions in the vagus nerve and so argued against a vagal route (Arotcarena et al., Brain 2020;143:1462–1475); a 2019 mouse study found that cutting the vagus prevented gut-to-brain spread (Kim et al., Neuron, via a search summary).

Sources

• Holmqvist et al., Acta Neuropathol 2014;128:805–820, DOI 10.1007/s00401-014-1343-6, PMID 25296989 (abstract via Europe PMC) · Alzforum paper page
• Arotcarena et al., Brain 2020, DOI 10.1093/brain/awaa096 (a 2025 correction to this paper exists, DOI 10.1093/brain/awaf023)
• Not yet verified: the number of rats, time points and doses; whether pathology or neuron loss followed; the authors' institutions; the Kim 2019 details (only a search summary seen). No correction or retraction was found for Holmqvist 2014 (Crossref, Europe PMC); PubPeer could not be reached.