Fibril-seeding (PFF) models

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

Laura Volpicelli-Daley, Kelvin Luk, Virginia Lee and John Trojanowski at the University of Pennsylvania. NIH/NINDS grants are listed for both papers.

What happened

In 2011 (Neuron 72:57–71) the team grew fibrils from full-length and truncated human synuclein and added them to cultured mouse neurons. Within days the neurons' own synuclein formed insoluble, phosphorylated inclusions resembling Lewy bodies: in nerve fibres after about 4 days, in cell bodies by 7 days, and widespread by 10 days. Synapse proteins fell, and about 40% fewer neurons were left by day 14. Neurons from synuclein-knockout mice formed no inclusions and did not die, so the neuron's own synuclein was needed. In 2012 (Science 338:949–953) Luk injected the fibrils into one striatum of normal mice (controls got saline or monomeric synuclein). Pathology spread to connected regions, nigral dopamine neurons on the injected side fell about 15% at 90 days and about 35% at 180 days, with none lost at 30 days (the neighbouring ventral tegmental area was spared), and movement tests worsened. Group sizes were small: neuron counts used 3–4 mice per group.

Why it moved us toward a cure

It turned the prion-like spread idea (landmark 8) into a repeatable experiment in ordinary animals, and let researchers test whether blocking spread protects neurons. It is now the standard test bed for anti-spread drugs; an anti-synuclein antibody, prasinezumab, is in Phase 3 (see the README).

Outcome

Advanced as a research tool: other labs reproduced it, for example Paumier et al. (Neurobiol Dis 2015) in rats, where fibril injection gave inclusions and nigral loss. No correction or retraction was found for either paper. Caveats: the fibrils are artificial and injected directly into the brain, so it does not show how disease starts in people, and the 2011 paper did not show neurons release fibrils to spread it. Spread to connected brain regions was shown in mice in 2012.

Sources

• Volpicelli-Daley et al., Neuron 2011;72:57–71, DOI 10.1016/j.neuron.2011.08.033
• Paumier et al., Neurobiol Dis 2015;82:185–199, DOI 10.1016/j.nbd.2015.06.003
• Alzforum, "Modeling Sporadic PD in a Dish?" · ScienceDaily on Volpicelli-Daley 2011
• Luk et al., Science 2012;338:949–953, DOI 10.1126/science.1227157 (PMC3552321) · ScienceDaily on Luk 2012
• Not yet verified: the press release gives larger loss figures (about half at six months) than the paper's counts (about 35%), and the paper's figures are used here; whether any drug moved to trials mainly on PFF-model data; Paumier 2015 was read through a search summary only; PubPeer not checked.