Lewy bodies in grafts: prion-like spread

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

Jeffrey Kordower, Warren Olanow and colleagues (Nat Med 14:504–506); Jia-Yi Li, Patrik Brundin, Olle Lindvall and colleagues (Nat Med 14:501–503); both 2008. Kelvin Luk, Virginia Lee and John Trojanowski (Science 338:949–953, 2012). Funders of the 2008 papers were not checked; Luk 2012 lists US NIH extramural support.

What happened

Three patients with Parkinson's who had fetal midbrain grafts 11 to 16 years earlier were examined after death. Li et al. described two (11 and 16 years) with alpha-synuclein-positive Lewy bodies inside some donor neurons; Kordower et al. described one (14 years) with Lewy body-like inclusions and less dopamine transporter staining in the graft. The disease had apparently passed from the host brain into healthy transplanted cells. Li noted that most grafted cells looked healthy and the patients kept symptom relief. A third paper in the same issue found no such pathology in five patients 9 to 14 years after grafting (Mendez et al., Nat Med 14:507–509), so the finding was not seen in every case. In 2012, a single injection of synthetic alpha-synuclein fibrils into the striatum of healthy mice seeded Lewy-like pathology in connected regions, followed by progressive loss of dopamine neurons in the substantia nigra and motor deficits.

Why it moved us toward a cure

The grafts came from the first fetal transplants (landmark 3), and the inclusions were stained for alpha-synuclein, the protein Lewy bodies are made of (landmark 5). The patterns also echoed Braak's idea of an ordered spread (landmark 6). Together these suggested misfolded alpha-synuclein passes from cell to cell like a prion. That made blocking the spread, for example with antibodies, a direct strategy for slowing the disease.

Outcome

Open. Spread is well established in models, but the graft evidence is from three patients, with five others showing none, and whether blocking spread helps patients is unproven. The antibody prasinezumab missed its main goals in two Phase 2 trials and is now in the PARAISO Phase 3 (landmark 63). No correction or retraction was found for the three papers (Crossref, Europe PMC).

Sources

• Kordower et al., Nat Med 2008 (DOI)
• Li et al., Nat Med 2008 (DOI)
• Luk et al., Science 2012 (PubMed 23161999, DOI 10.1126/science.1227157)
• Mendez et al., Nat Med 2008;14:507–509, DOI 10.1038/nm1752 (PubMed 18391961)
• Not yet verified: funders of the Kordower, Li and Mendez papers; full texts (abstracts read); later autopsy reports of graft pathology after 2008.