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| Item Type: | Preprint |
|---|---|
| Title: | Expression of a modified astrocytic glutamate transporter alleviates Huntington’s hypokinesia, promotes synaptic glutamate clearance and counteracts potentially adverse EAAT2 interactions |
| Creators Name: | Hirschberg, S., Dvorzhak, A., Rasooli-Nejad, S.M.A., Angelov, S., Kirchner, M., Mertins, P., Lättig-Tünnemann, G., Harms, C., Schmitz, D. and Grantyn, R. |
| Abstract: | Rapid removal of glutamate from the sites of glutamate release is an essential step in excitatory synaptic transmission. Despite many years of research, the molecular mechanisms underlying the intracellular regulation of glutamate transport at tripartite synapses have remained unclear. This limits the options for pharmacological treatment of motor disorders associated with glutamate excitotoxicity. Therefore, using the Q175 mouse model of Huntington’s disease (HD), we explored the effects of structural changes in the astrocytic excitatory amino acid transporter type 2 (EAAT2). We report that expression of a C-terminal-modified variant of EAAT2 can alleviate the symptoms of hypokinesia in mice with already advanced HD. At a cellular level, this beneficial outcome correlated with faster synaptic glutamate clearance, higher astrocytic glutamate uptake and larger amounts of native EAAT2 protein. Proteomics data indicate a partial reversal of HD-induced changes in the EAAT2 interactor spectrum. Thus, astrocytic glutamate transport remains a target for therapeutic intervention. |
| Keywords: | Huntington's Disease, EAAT2 Interaction Proteomics, Hypokinesia, Corticostriatal Synaptic Transmission, Glutamate Clearance, Synaptic Targeting of EAAT2, Animals, Mice |
| Source: | bioRxiv |
| Publisher: | Cold Spring Harbor Laboratory Press |
| Article Number: | 2020.09.17.302158 |
| Date: | 26 March 2021 |
| Official Publication: | https://doi.org/10.1101/2020.09.17.302158 |
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