Synuclein helps assemble synapse machinery

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

Jacqueline Burré, Manu Sharma, Theodoros Tsetsenis, Vladimir Buchman, Mark Etherton and Thomas Südhof (senior author), at Stanford University and the Howard Hughes Medical Institute. Funders were not read.

What happened

Nerve endings release neurotransmitters by repeatedly assembling and taking apart SNARE complexes, protein bundles that pull a packet of chemicals against the cell surface so it can fuse and discharge. The team found that alpha-synuclein binds the SNARE protein VAMP2 (synaptobrevin-2) and promotes SNARE assembly, a "non-classical" chaperone activity. Mice lacking all three synuclein genes (alpha, beta and gamma) looked normal when young, then made fewer SNARE complexes as they aged, developed neurological problems and died early (Alzforum: most survived past one year). Science 329:1663–1667, published online 26 Aug 2010 and in print 24 Sep 2010.

Why it moved us toward a cure

Most synuclein strategies aim to cut it or clear it (landmark 29, landmark 14). This paper gave a normal function to weigh against that: if synuclein maintains the synapse, a clump might both add toxicity and remove a needed helper, and over-lowering could carry its own risk. Südhof described the role as an "insurance policy" that matters with age. That is a reading, not a demonstrated risk in people.

Outcome

Open. Independent scientists quoted by Alzforum were cautious. Alzforum reports that brain-slice recordings showed no change in synaptic transmission; Subhojit Roy said his lab sees release deficits with modestly raised synuclein and asked what defect causes the knockout phenotype if not reduced release; Mark Cookson (NIA) called the role "more modulatory". The study did not itself test neurodegeneration in Parkinson's. The normal function of the protein is still being worked out. Europe PMC lists no correction or retraction, and no Masliah authorship. Independent replication of the chaperone claim was not searched for.

Sources

• Burré et al., Science 2010;329(5999):1663–1667, DOI 10.1126/science.1195227 (abstract) · author list and date, Weill Cornell record
• Alzforum, "α-Synuclein's Day Job: To Chaperone SNARE Complexes?" (independent comments and caveats)
• Europe PMC record
• Not yet verified: the full text; which cell types and doses were used; any evidence that lowering synuclein in humans reduces SNARE assembly; independent replications of the chaperone finding; funders.