. Extracellular α-synuclein levels are regulated by neuronal activity. Mol Neurodegener. 2018 Feb 22;13(1):9. PubMed.


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  1. The authors compared a 30 kDa to a 1,000 kDa MW cutoff dialysis membrane during brain microdialysis (Fig. 2 l-o), and suggest that the form of α-synuclein they found in ISF was >30 kDa, i.e., good passage of recombinant monomers (14 kDa) but not this natural α-synuclein species. They then sized the latter by non-denaturing SEC, suggesting a rather sharp peak at ~60-70 kDa.

    This could be consistent with a physiological tetramer such as we and others have described in neurons and erythrocytes in the last few years (e.g., Bartels et al., 2011Dettmer et al., 2015), though the authors do not link their findings to this earlier work. 

    However, there are two caveats: a) SEC is known not to distinguish α-synuclein monomers from tetramers well, due to the large hydrodynamic radius of the monomer, which leads to its elution at ~60 kDa on SEC columns; and b) the normal tetramers we have described are detectable intraneuronally by intact-cell cross-linking and apparently require “molecular crowding” for stability, such that cell lysis or brain homogenization largely depolymerizes the tetramer in dilute solution (Dettmer et al.,  2013). 

    We speculate that a small lipid moiety binds to the α-synuclein tetramer intracellularly to help stabilize it, and this “limiting factor” is diluted/lost upon cell lysis (see also Kim et al., 2018).​ Nevertheless, the species the authors describe in ISF is presumably a normal form of α-synuclein (the mice are wild-type and healthy), so it is possible that a lipid moiety stays bound to the tetramer during physiological secretion by neurons, which would be an important discovery. So, the existence of a potentially metastable tetramer in normal ISF is intriguing although not proven definitively here. Cross-linking a sample of ISF and then running it on denaturing SDS-PAGE could reveal whether the ISF species then runs at 60 kDa and can thus be assumed to be a tetramer in vivo.

    Parenthetically, the authors emphasize the role of abnormal extracellular α-synuclein species being physically transported from neuron to neuron during PD, but a) their species is normal, and b) this hypothesis for PD is not consistent with all available evidence (Walsh and Selkoe, 2016). 


    . α-Synuclein occurs physiologically as a helically folded tetramer that resists aggregation. Nature. 2011 Aug 14;477(7362):107-10. PubMed.

    . Parkinson-causing α-synuclein missense mutations shift native tetramers to monomers as a mechanism for disease initiation. Nat Commun. 2015 Jun 16;6:7314. PubMed.

    . In vivo cross-linking reveals principally oligomeric forms of α-synuclein and β-synuclein in neurons and non-neural cells. J Biol Chem. 2013 Mar 1;288(9):6371-85. Epub 2013 Jan 14 PubMed.

    . GBA1 deficiency negatively affects physiological α-synuclein tetramers and related multimers. Proc Natl Acad Sci U S A. 2018 Jan 23;115(4):798-803. Epub 2018 Jan 8 PubMed.

    . A critical appraisal of the pathogenic protein spread hypothesis of neurodegeneration. Nat Rev Neurosci. 2016 Apr;17(4):251-60. PubMed.

    View all comments by Dennis Selkoe
  2. The Yamada paper clearly demonstrates that neuronal activity regulates release of α-synuclein. They use a similar microdialysis system that we have used to show that activity regulates Aβ, and that Dr. Yamada has used to show activity regulates tau.

    Activity seems to have a larger effect on α-synuclein release than it does for either Aβ or tau. The latrotoxin experiments are particularly interesting, demonstrating that synaptic vesicle exocytosis alone is sufficient to increase α-synuclein levels.

    Of course the missing component here is HOW activity causes α-synuclein release. It is a synaptic vesicle-associated protein, but on the cytoplasmic side of the membrane, so there is no reason it would have to get secreted at all. Figuring out how it gets out of the cell will be very important. And of course what species of α-synuclein is secreted, monomer or aggregates, which has implications for synuclein propogation between cells.

    View all comments by John Cirrito

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  1. When Neurons Get Excited, They Spill α-Synuclein