Synuclein travels in vesicles

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

Evangelia Emmanouilidou, Kostas Vekrellis (last author), Leonidas Stefanis and colleagues (2010); Karin Danzer, Pamela McLean (last author) and colleagues (Massachusetts General Hospital, 2012); Annika Stuendl, Anja Schneider (last author) and colleagues (University Medicine Göttingen, 2016). Funders were not read; Europe PMC lists NIH extramural support for the 2010 and 2012 papers.

What happened

Alpha-synuclein was long thought to stay inside cells. Emmanouilidou showed that cultured SH-SY5Y cells (a human neuroblastoma line) engineered to make synuclein secrete it in a calcium-dependent way, in vesicles with the features of exosomes, and that the medium harmed recipient neuronal cells. J Neurosci 30(20):6838–6851, 19 May 2010. In 2012 Danzer's group, using a protein-fragment assay that lights up when two synuclein molecules meet, found oligomers outside cells either free or bound to exosomes; the exosome-bound ones were more readily taken up and caused more toxicity, and the lab saw that autophagy shaped the release. Mol Neurodegener 7:42. In 2016 Stuendl isolated exosomes from spinal fluid of patients with Parkinson's disease, dementia with Lewy bodies, progressive supranuclear palsy and neurological controls; those from Parkinson's and Lewy body dementia patients triggered synuclein oligomerisation in a reporter cell line in a dose-dependent way. Brain 139(2):481–494.

Why it moved us toward a cure

It supplied a physical route for cell-to-cell spread besides direct fibril uptake (landmark 43, landmark 51). It also suggested that boosting autophagy or blocking exosome release might slow spread, and that spinal-fluid vesicles could carry a disease signal; compare the seed assays in landmark 9.

Outcome

Open. On Alzforum, Lawrence Rajendran noted that the 2010 paper did not show that exosome-bound synuclein is itself toxic or taken up by neighbouring cells; the first author agreed that toxicity of the exosome-associated fraction was not tested and that internalisation by neuronal cells was not seen. Tim West queried one mass-spectrometry peptide that matched beta-synuclein at two residues, and Vekrellis replied with a second spectrum he said was unique to alpha-synuclein. Most experiments were in cultured cells. Europe PMC lists no correction or retraction for the three papers. How much spread in human brains travels in vesicles remains unsettled.

Sources

• Emmanouilidou et al., J Neurosci 2010;30:6838–6851, DOI 10.1523/JNEUROSCI.5699-09.2010 (citation) · Alzforum discussion thread
• Danzer et al., Mol Neurodegener 2012;7:42, DOI 10.1186/1750-1326-7-42 (abstract) · authors
• Stuendl et al., Brain 2016;139:481–494, DOI 10.1093/brain/awv346
• Not yet verified: the Alzforum comments were read in summary only; the neuron-to-neuron uptake of exosomal synuclein in living animals; exosomes' share of total secreted synuclein; replication of the spinal-fluid result; whether any treatment targeting vesicle release is in trials.