Synuclein strains

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

Wouter Peelaerts and Veerle Baekelandt (KU Leuven, Laboratory for Neurobiology and Gene Therapy), with Luc Bousset and Ronald Melki (CNRS, Paris-Saclay Institute of Neuroscience) who made the structurally defined assemblies, and colleagues (Nature, 18 June 2015). Funders were not checked.

What happened

The team made three structurally defined forms of alpha-synuclein: oligomers (small clusters), fibrils, and "ribbons" (a differently folded assembly). They injected them into rat substantia nigra, with or without extra synuclein production. Oligomers and ribbons spread more widely than fibrils. Fibrils were the most toxic, killing dopamine neurons and causing movement problems. Only ribbons produced large Lewy-like deposits of phosphorylated synuclein, and with synuclein overexpression they also produced deposits in oligodendroglia (the brain's insulating cells), a feature of multiple system atrophy (a related disease), though commenters noted it is unclear whether these resemble the true glial inclusions of that disease. Fibrils affected only neurons. Material extracted from the brains differed in resistance to the enzyme proteinase K, suggesting the injected form shapes the resulting aggregate. Injected into the blood, strains also reached the brain. Nature 522(7556):340-344.

Why it moved us toward a cure

It adds a reason why one protein can cause several diseases and why Parkinson's patients differ: prion-style strains. It reinforced the spread model (landmark 51) and anticipated patient-derived fold differences (landmark 27) and the seed-amplification test (landmark 9). Practically, drugs and antibodies may need to hit the relevant strain.

Outcome

Open. No correction or retraction was found (Crossref, Europe PMC); PubPeer could not be reached. As Günter Höglinger and colleagues noted in an Alzforum comment, it remains a hypothesis: oligomers showed no toxicity here, which conflicts with other studies; it is unknown whether these strains exist in patients; and lab-to-lab differences in preparation make results hard to compare.

Sources

• Peelaerts et al., Nature 2015;522:340-344, DOI 10.1038/nature14547
• Alzforum news and comment
• Not yet verified: the replication of the strain-specific pathology by an independent lab; whether patient-derived strains match these lab forms; funders. The paper has three published comments (Nature 522:296, Nat Rev Neurol 2015, Mov Disord 2015).