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Dissertation
Ischemia-induced ubiquitination of GLT-1 mediates aberrant trafficking and impaired glutamate uptake
Doctor of Philosophy (Ph.D.), Drexel University
May 2026
DOI:
https://doi.org/10.17918/00011343
Abstract
Glutamate transporters are essential for maintaining central nervous system (CNS) homeostasis by clearing extracellular glutamate after synaptic transmission. Dysregulation of these transporters contributes to glutamate-mediated excitotoxicity in numerous neurological disorders, including ischemic stroke, highlighting them as promising therapeutic targets. However, the regulatory response of these transporters following ischemic insult remains poorly defined. In this work, using an oxygen-glucose deprivation model in rat primary glial cultures, we report aberrant trafficking of the astrocytic glutamate transporter GLT-1 following ischemic insult. This response is characterized by increased transporter internalization and degradation, accompanied by reduced glutamate uptake capacity. Focusing on post-translational modifications (PTMs), we found that GLT-1 ubiquitination is markedly increased after ischemic insult and coincides with transporter internalization. Importantly, disrupting this ubiquitination interaction through mutation of C-terminal GLT-1 lysine residues restores GLT-1 surface expression and rescues glutamate uptake capacity through preventing early endosome 1 (EEA1)-mediated internalization. Additionally, we report that inhibition of C-terminal GLT-1 PTMs confers neuroprotection following ischemic insult in organotypic rat hippocampal slices. Together, these findings demonstrate that ischemia-induced dysregulation of GLT-1 trafficking plays a critical role in impaired glutamate clearance and cellular recovery, highlighting GLT-1 ubiquitination as a potential therapeutic target for ischemic injury.
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Details
- Title
- Ischemia-induced ubiquitination of GLT-1 mediates aberrant trafficking and impaired glutamate uptake
- Creators
- Simran K. Gill
- Contributors
- Andreia Mortensen (Advisor)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University
- Number of pages
- 122 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- College of Medicine; Pharmacology and Physiology; Drexel University
- Other Identifier
- 991022176276304721