Spinelli KJ, Taylor JK, Osterberg VR, Churchill MJ, Pollock E, Moore C, Meshul CK, Unni VK.
Presynaptic alpha-synuclein aggregation in a mouse model of Parkinson's disease.
J Neurosci. 2014 Feb 5;34(6)
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These studies from Vivek Unni’s lab reiterate the importance of focusing on the synaptic accumulation and aggregation of α-synuclein, rather than somatic Lewy bodies. Specifically, they strengthen the hypothesis that small increments in α-synuclein are detrimental to synapses, and advocate that a rigorous evaluation of normal and abnormal forms of synaptic α-synuclein is needed to really move the field forward.
The in-vivo studies by Spinelli et al. are technically challenging and are a valuable contribution to the field. They highlight the immobile fraction of synaptic α-synuclein that we and others have proposed, and also give insights into the physiological state of α-synuclein in cell bodies and synapses. The existence of an extremely immobile α-synuclein pool—presumably composed of α-synuclein aggregates—is quite interesting, and makes one wonder about the consequences of this aggregation upon synaptic physiology.
In light of recent studies suggesting that α-synuclein may physiologically exist as helically folded tetramers, and that these conformations resist aggregation, it will be interesting to further understand the repertoire of synaptic “aggregates/oligomers/multimers/tetramers.” Are there both “physiologic” and “pathologic” α-synuclein conformations at synapses? If so, how are these “good” and “bad” pools regulated in normal and abnormal states? A few years ago I organized a mini-symposium at SfN titled “Alpha synuclein—the Good, the Bad and the Ugly.” Clearly my timing was off and it is only now that we may be starting to frame the right questions. Does Good equal helical-tetramers, Bad equal monomers, and Ugly equal other higher-order aggregates? Maybe time will tell!
This paper by Spinelli et al. fits well in my concept that presynaptic alpha-synuclein aggregates are pathophysiologically linked to the diseases PD, PDD, and DLB. It’s interesting to know that in-vivo multiphoton imaging may be able to monitor presynaptic alpha-synuclein aggregation. This may indeed have implications for drug development.