Translational enhancers of EAAT2: therapeutic implications for neurodegenerative disease

Abstract

Glutamate excitotoxicity contributes to the neuronal injury and death associated with many neurodegenerative diseases. The glutamate transporter EAAT2, which is primarily localized on astrocytic processes, facilitates glutamate clearance from synapses, thus preventing neuronal damage. In this issue of the JCI, Kong et al. characterize a compound that upregulates EAAT2 translation, thereby increasing glutamate uptake by glial cells. Furthermore, this strategy for alleviating excitotoxicity was found to be beneficial in mouse models of both amyotrophic lateral sclerosis (ALS) and epilepsy, suggesting that future development in this chemical series may lead to much-needed treatments for these disorders.

Figure 1. LDN/OSU-021230 upregulates EAAT2 expression in astrocytes.

(A) In many neurodegenerative diseases, excess glutamate (red circles) causes damage to neurons (aqua), which can be mitigated by glutamate uptake by astrocytes (pink). (B) LDN/OSU-021230 increases glutamate uptake through the upregulation of EAAT2 receptors on astrocytic processes. Following LDN/OSU-021230 treatment, PKC becomes activated. This activation is required for phosphorylation of the translational regulator YB-1. LDN/OSU-021230 enhances the interaction of YB-1 with EAAT2 mRNA and upregulates the translation of EAAT2 protein. EAAT2 localizes to the plasma membrane, where it facilitates glutamate uptake by the cell, thus reducing glutamate excitotoxicity.