Synuclein oligomers are toxic

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

Beate Winner (Salk Institute, later Erlangen), Roberto Jappelli, Samir Maji, Paula Desplats, Eliezer Masliah (UC San Diego), Fred Gage (Salk), Roland Riek (ETH Zurich, last author) and 12 others. Funders listed: NIH, Swiss National Science Foundation, California Institute for Regenerative Medicine, Picower Foundation, Lookout Fund, Michael J. Fox Foundation and the Alexander von Humboldt Foundation. Masliah's listed roles were designing the research and analysing data.

What happened

Using structural modelling, the team designed alpha-synuclein variants (E57K, E35K) that stall as oligomers, and another (a truncated form, residues 30–110) that quickly forms fibrils. Lentiviral vectors carried each into the right substantia nigra of adult rats. Three weeks later (four rats per group), stereological counts of tyrosine hydroxylase-positive (dopamine) neurons showed about 51% loss with E57K and about 50% with E35K, versus about 9% (not significant) for the fibril-former. Familial mutants A30P and E46K caused about 38–40% loss; A53T about 17%. Toxicity tracked SDS-stable trimers in the membrane fraction. PNAS 108(10):4194–4199, 8 March 2011.

Integrity check. Masliah is a middle author. The paper is not on the Alzforum list of Masliah papers with PubPeer links or corrections, and I found no correction, expression of concern or retraction (checked 19 Oct 2026; PNAS page itself could not be opened). Its reference list marks one cited paper (Tsigelny 2008) as retracted.

Why it moved us toward a cure

It supported a hypothesis now guiding drug design: the dangerous forms are intermediate, membrane-active oligomers, so removing visible aggregates may not be enough. It helps explain why antibodies and small molecules are tested against several synuclein species (landmark 63, landmark 64, landmark 65). It complements the structural work in landmark 27 and the strain idea in landmark 60.

Outcome

Open. The experiment has real limits: the constructs were engineered, expression with the main promoter was about eightfold above endogenous synuclein in rat nigra (a weaker promoter still exceeded levels in patients with a synuclein gene triplication), groups were four animals, and the trimer-toxicity link is a correlation. No oligomer-selective drug has yet shown clinical benefit in the trials listed above (minzasolmin, an anti-misfolding pill, failed in Phase 2). Which natural oligomer actually kills human neurons is unsettled. I found no independent replication of the rat result; the follow-up E57K transgenic mouse paper (Rockenstein et al., Brain 2014) shares authors including Winner, Riek and Gage.

Sources

• Winner et al., PNAS 2011;108:4194–4199, DOI 10.1073/pnas.1100976108 (full text, Brescia repository) · citation record · abstract
• Alzforum paper entry
• Full text, PMC3053976 (affiliations, funding, numbers) · Alzforum list of Masliah papers
• Not yet verified: independent replication in other labs (none found); whether the oligomers modelled here exist in patients' brains; any later critical commentary; PNAS page notice status.