5 May 2000. 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.
Reference:Murphy DD, Rueter SM, Trojanowski JQ, Lee VM. Synucleins are developmentally expressed, and a-synuclein regulates the size of the presynaptic vesicular pool in primary hippocampal neurons. J Neurosci 2000 May 1;20(9):3214-3220. Abstract