The neuronal peptide α-synuclein is an important constituent of the Lewy bodies, pathological hallmarks of the Lewy body variant of Alzheimer's disease, as well as of Parkinson's and several other neurodegenerative diseases. Beyond that, not much is known about its role in pathogenesis. Regarding its normal physiologic role there is also little data beyond the fact that it is found in presynaptic terminals. In this month's Journal of Neuroscience, Virginia Lee, Diane Murphy and colleagues at the University of Pennsylvania present results suggesting that one function of α-synuclein may be to regulate the pool of synaptic vesicles that store neurotransmitter molecules awaiting release.

The researchers used light and electron microscopy, along with immunocytochemistry and protein biochemistry, to examine primary hippocampal neuronal cultures through the three weeks required for these neurons to develop mature cytoarchitecture and synaptic contacts. In the first part of the study they addressed an earlier suggestion that α-synuclein has a role in the development of synapses. Their findings-that the peptide (along with its sibling, β-synuclein) appears only after the formation of synapses, and after the appearance of other presynaptic proteins-argue that α-synuclein is involved in the maintenance, rather than development, of synapses. This was supported by the finding that in mature, three-week-old neurons, α-synuclein was only found in synapses.

The second part of the study involved introducing an anti-sense oligonucleotide to decrease the expression of α-synuclein in the cultures. The resulting neurons formed synapses but these showed marked reductions in the pool of vesicles inside the synapse and away from the membrane (though there were normal densities of vesicles at the synaptic membranes).

"The data presented here may signify that the availability of vesicles for release in familial and sporadic Parkinson's disease brains could be compromised by α-synuclein pathologies, thereby leading to impaired synaptic function and degeneration," write the authors.—Hakon Heimer


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Primary Papers

  1. . Synucleins are developmentally expressed, and alpha-synuclein regulates the size of the presynaptic vesicular pool in primary hippocampal neurons. J Neurosci. 2000 May 1;20(9):3214-20. PubMed.