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<a href="http://doi.org/10.1523/JNEUROSCI.1871-20.2020" target="_blank" rel="noreferrer noopener">http://doi.org/10.1523/JNEUROSCI.1871-20.2020</a>
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1529-2401 0270-6474
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Update Year & Number
February 2021 List
NEOMED College
NEOMED College of Medicine
NEOMED Department
Department of Integrative Medical Sciences
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Title
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α-Synuclein Oligomers Induce Glutamate Release from Astrocytes and Excessive Extrasynaptic NMDAR Activity in Neurons, Thus Contributing to Synapse Loss.
Date
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2021
2021-01-22
Subject
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neuron loss; synapse loss
Creator
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Trudler D;Sanz-Blasco S;Eisele YS;Ghatak S;Bodhinathan K;Akhtar MW;Lynch WP;Piña-Crespo JC;Talantova M;Kelly JW;Lipton SA
Description
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Synaptic and neuronal loss are major neuropathological characteristics of Parkinson's disease (PD). Misfolded protein aggregates in the form of Lewy bodies, comprised mainly of α-synuclein (αSyn), are associated with disease progression, and have also been linked to other neurodegenerative diseases, including Lewy body dementia (LBD), Alzheimer's disease (AD, and Frontotemporal dementia (FTD). However, the effects of αSyn and its mechanism of synaptic damage remain incompletely understood. Here, we show that αSyn oligomers induce Ca(2+)-dependent release of glutamate from astrocytes obtained from male and female mice, and that mice overexpressing αSyn manifest increased tonic release of glutamate in vivo In turn, this extracellular glutamate activates glutamate receptors, including extrasynaptic NMDA receptors (eNMDARs), on neurons both in culture and in hippocampal slices of αSyn-overexpressing mice. Additionally, in patch-clamp recording from outside-out patches, we found that oligomerized αSyn can directly activate eNMDARs. In organotypic slices, oligomeric αSyn induces eNMDAR-mediated synaptic loss, which can be reversed by the drug NitroSynapsin. When we expose human induced pluripotent stem cell (hiPSC)-derived cerebrocortical neurons to αSyn, we find similar effects. Importantly, the improved NMDAR antagonist NitroSynapsin, which selectively inhibits extrasynaptic over physiological synaptic NMDAR activity, protects synapses from oligomeric αSyn-induced damage in our model systems, thus meriting further study for its therapeutic potential.SIGNIFICANCE STATEMENTLoss of synaptic function and ensuing neuronal loss is associated with disease progression in Parkinson's disease (PD), Lewy body dementia (LBD), and other neurodegenerative diseases. However, the mechanism of synaptic damage remains incompletely understood. α-Synuclein (αSyn) misfolds in PD/LBD, forming Lewy bodies and contributing to disease pathogenesis. Here, we found misfolded/oligomeric αSyn releases excessive astrocytic glutamate, in turn activating neuronal extrasynaptic NMDA receptors (eNMDARs), thereby contributing to synaptic damage. Additionally, αSyn oligomers directly activate eNMDARs, further contributing to damage. While the FDA-approved drug memantine has been reported to offer some benefit in PD/LBD (Hershey and Coleman-Jackson, 2019), we find the improved eNMDAR antagonist NitroSynapsin ameliorates αSyn-induced synaptic spine loss, providing potential disease-modifying intervention in PD/LBD.
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<a href="http://doi.org/10.1523/JNEUROSCI.1871-20.2020" target="_blank" rel="noreferrer noopener">10.1523/JNEUROSCI.1871-20.2020</a>
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journalArticle
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The Journal Of Neuroscience
2021
Akhtar MW
Bodhinathan K
Department of Integrative Medical Sciences
Eisele YS
February 2021 List
Ghatak S
journalArticle
Kelly JW
Lipton SA
Lynch WP
NEOMED College of Medicine
neuron loss
Piña-Crespo JC
Sanz-Blasco S
synapse loss
Talantova M
The Journal of Neuroscience
Trudler D