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dc.contributor.authorSong, Yuyu  Concept link
dc.identifier.citationSong, Y. (2020). Synaptic actions of amyotrophic-lateral-sclerosis-associated G85R-SOD1 in the squid giant synapse. Eneuro, ENEURO.0369-19.2020.en_US
dc.description© The Author(s), 2020. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Song, Y. Synaptic actions of amyotrophic-lateral-sclerosis-associated G85R-SOD1 in the squid giant synapse. Eneuro, (2020): ENEURO.0369-19.2020, doi: 10.1523/ENEURO.0369-19.2020.en_US
dc.description.abstractAltered synaptic function is thought to play a role in many neurodegenerative diseases, but little is known about the underlying mechanisms for synaptic dysfunction. The squid giant synapse (SGS) is a classical model for studying synaptic electrophysiology and ultrastructure, as well as molecular mechanisms of neurotransmission. Here, we conduct a multidisciplinary study of synaptic actions of misfolded human G85R-SOD1 causing familial Amyotrophic Lateral Sclerosis (fALS). G85R-SOD1, but not WT-SOD1, inhibited synaptic transmission, altered presynaptic ultrastructure, and reduced both the size of the Readily Releasable Pool (RRP) of synaptic vesicles and mobility from the Reserved Pool (RP) to the RRP. Unexpectedly, intermittent high frequency stimulation (iHFS) blocked inhibitory effects of G85R-SOD1 on synaptic transmission, suggesting aberrant Ca2+ signaling may underlie G85R-SOD1 toxicity. Ratiometric Ca2+ imaging showed significantly increased presynaptic Ca2+ induced by G85R-SOD1 that preceded synaptic dysfunction. Chelating Ca2+ using EGTA prevented synaptic inhibition by G85R-SOD1, confirming the role of aberrant Ca2+ in mediating G85R-SOD1 toxicity. These results extended earlier findings in mammalian motor neurons and advanced our understanding by providing possible molecular mechanisms and therapeutic targets for synaptic dysfunctions in ALS as well as a unique model for further studies.en_US
dc.description.sponsorshipGrass Foundation, HHMI, MGH Jack Satter Foundation, Harvard University ALS and Alzheimer's Endowed Research Fund, Harvard Brain Science Initiative.en_US
dc.publisherSociety for Neuroscienceen_US
dc.rightsAttribution 4.0 International*
dc.subjectgiant synapseen_US
dc.subjectsynaptic vesiclesen_US
dc.titleSynaptic actions of amyotrophic-lateral-sclerosis-associated G85R-SOD1 in the squid giant synapseen_US

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Attribution 4.0 International
Except where otherwise noted, this item's license is described as Attribution 4.0 International