Extra copies of the synuclein gene cause Parkinson's

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

Andrew Singleton (National Institute on Aging, Bethesda), Matthew Farrer, John Hardy, Katrina Gwinn-Hardy and 18 co-authors (22 in all). Funders were not checked.

What happened

In a large family (the Iowa kindred, named in the authors' later clinical report) with dominantly inherited Parkinson's and no SNCA point mutation, linkage mapping placed the disease region on chromosome 4 around SNCA. Quantitative PCR and FISH showed the region is triplicated (about 2 Mbp, 17 genes), and the extra gene dose was judged the most likely explanation. Science 302:841, 31 October 2003. In 2004 two papers in The Lancet found whole-gene duplications (two copies instead of three) in families with a milder, more typical Parkinson's: one French family (Chartier-Harlin et al.) and two patients (Ibáñez et al.), showing a dose effect. This differs from landmark 4, where a changed protein caused disease; here the protein is normal but there is too much of it.

Why it moved us toward a cure

It is the main rationale for lowering alpha-synuclein by any route: antisense drugs, antibodies or other methods.

Outcome

Advanced. Synuclein-lowering strategies are in trials, but none has shown a clinical benefit yet.

Sources

• Singleton et al., Science 2003, DOI 10.1126/science.1090278
• Alzforum, "Synuclein and Parkinson's – It's All in the Dose"
• Chartier-Harlin et al., Lancet 2004;364:1167–1169, DOI 10.1016/S0140-6736(04)17103-1, PMID 15451224 · Ibáñez et al., Lancet 2004;364:1169–1171, DOI 10.1016/S0140-6736(04)17104-3, PMID 15451225
• Gwinn et al., Mov Disord 2011;26:2134–2136, DOI 10.1002/mds.23776, PMID 21656851 ("Iowa kindred")
• Not yet verified: that the Science family is the same kindred as in Gwinn 2011 (title and shared authors say so; the Science text was not read); the family's size; the linkage, qPCR and FISH methods (from the earlier text; Science has no abstract and Alzforum was not checked for them).