Bookshelf

Glutamate-mediated excitotoxicity in ALS. A. In ALS, the astrocytic glutamate transporter GLT-1 is downregulated, leading to an impaired glutamate uptake, and the TNF-α/TNFR1/NF-κB pathway modulates its expression levels (48). Membralin is reduced in the spinal cord of ALS patients and ALS mouse models, and its deletion was shown to suppress GLT-1 expression through the TNF-α/TNFR1/NF-κB pathway (49). AEG-1 is upregulated in ALS and its silencing restores GLT-1 expression and inhibits NF-κB signaling (50). Caspase-3 cleaves GLT-1 and leads to the accumulation of a sumoylated C-terminus fragment, the CTE-SUMO1. The accumulation of this fragment causes astrocytes to alter their phenotypes and secrete toxic factors to MNs (51). Metabotropic glutamate receptors, such as mGluR5, are overexpressed in ALS, but their function was shown to be altered. PKC-ε is reduced in astrocytes, leading to the generation of atypical Ca²⁺ oscillations and impaired glutamate uptake (58, 59). B. Glutamate release has been shown to be abnormally increased in ALS. Exposure to GABA or glycine leads to an abnormal GAT1 or GlyT1/2-mediated glutamate release (62). Astrocytes also release high levels of glutamate through the upregulation of cystine/glutamate antiporters (xCT), in response to oxidative stress (65). Elevated symbiotic Cyanobacteria increases glutamate, linking gut microbiota to ALS (66). AEG-1, astrocyte elevated gene 1; ALS, amyotrophic lateral sclerosis; Ca²⁺, calcium; GABA, gamma aminobutyric acid; GAT1, GABA transporter type 1; GlyT, glycine transporter; GLT-1, glutamate transporter 1; mGluR, metabotropic glutamate receptor 5; MNs, motor neurons; NF-κB, nuclear factor-kappa B; PKC-ε, protein kinase C-epsilon; TNF-α, tumor necrosis factor alpha; TNFR1, tumor necrosis factor receptor 1; xCT, cystine/glutamate antiporters.