Figure 3.

L-Glu induction of neurotoxic protein aggregation mechanisms reported from in vitro and in vivo model studies. Excessive L-Glu exposure can potentially induce protein aggregation in neurons via an influence on transcription, translation, or protein post-translation modifications (PTMs). High L-Glu in the synaptic cleft induces excitotoxicity, resulting in high Ca²⁺ influx into neurons, and this triggers protein PTMs. PTMs arise via the activation of kinases and/or phosphatases affecting the levels of protein phosphorylation/dephosphorylation, calpain activation, or increased oxidative stress (ROS or RNS production). Excessive Ca²⁺ also causes mitochondrial dysfunction, resulting in ROS leakage, including O^2−•, which causes protein oxidation and protein carbonylation. O^2−• ions also interact with NO produced by nitric oxide synthase to produce reactive nitrogen species, such as ONOO⁻, which covalently modify proteins via protein nitration. L-Glu also increases the production of OH^•, which can also cause protein oxidation and oxidation of protein thiols. Collectively, these PTMs could alter protein conformation and promote misfolding and protein aggregation. Abbreviations: Ca²⁺, calcium ions; NO^•, nitric oxide; O^2−•, superoxide; OH^•, hydroxyl radical; ONOO⁻, peroxynitrite; PCC, protein carbonyl content; RNS, reactive nitrogen species; ROS, reactive oxygen species.