E3 ubiquitin ligase Nedd4‐2 exerts neuroprotective effects during endoplasmic reticulum stress

• Published in: Journal of neurochemistry 2022-03, Vol.160 (6), p.613-624
• Main Authors: Lodes, Daphne E., Zhu, Jiuhe, Tsai, Nien‐Pei
• Format: Article
• Language: English
• Subjects: Animals; Circuits; eIF2α; Endoplasmic reticulum; Endoplasmic Reticulum Stress; Endosomal Sorting Complexes Required for Transport - genetics; Excitability; Homeostasis; Mice; Mice, Knockout; Nedd4 Ubiquitin Protein Ligases - genetics; Nedd4 Ubiquitin Protein Ligases - metabolism; Nedd4‐2; Neurological diseases; Neuroprotection; Neuroprotective Agents; Phosphorylation; Proteins; seizure; Seizures; Seizures - chemically induced; Seizures - metabolism; stress; Substrates; Susceptibility; Synapses; Ubiquitin; Ubiquitin-protein ligase; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism; Ubiquitination
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/jnc.15567

The neural precursor cell expressed developmentally down‐regulated protein 4‐like (Nedd4‐2) is an E3 ubiquitin ligase critical for neurodevelopment and homeostasis of neural circuit excitability. While dysregulation of Nedd4‐2 has been linked to elevated seizure susceptibility through impaired ubiquitination of multiple direct substrates, it remains largely unclear whether Nedd4‐2 interconnects other cellular pathways that affect neuronal activity and seizure susceptibility. Here, we first showed that Nedd4‐2 associates with the endoplasmic reticulum (ER) and regulates the expression of multiple ER‐resident proteins. Furthermore, utilizing Nedd4‐2 conditional knockout mice, we showed that Nedd4‐2 is required for the maintenance of spontaneous neural activity and excitatory synapses following the induction of ER stress. When analyzing activation of the canonical pathways of ER stress response, we found that Nedd4‐2 is required for phosphorylation of eIF2α. While phosphorylation of eIF2α has been shown to reduce seizure susceptibility, attempts to facilitate phosphorylation of eIF2α in Nedd4‐2 conditional knockout mice failed to produce such a beneficial function, suggesting a role for Nedd4‐2 in integrating the ER stress response to modulate seizure susceptibility. Altogether, our study demonstrates neuroprotective functions of Nedd4‐2 during ER stress in neurons and could provide insight into neurological diseases in which the expression or activity of Nedd4‐2 is impaired. In Nedd4‐2 conditional knockout (cKO) cortical neuron cultures, induction of endoplasmic reticulum (ER) stress leads to a reduction in spontaneous neural activity, a reduction in excitatory synapses, and impaired eukaryotic initiation factor‐2α (eIF2α) phosphorylation. This impairment in eIF2α phosphorylation coupled with Nedd4‐2 deletion in mice causes a defect that impairs pharmacological reduction in seizure susceptibility mediated by salubrinal. These findings uncover neuroprotective functions of Nedd4‐2 during ER stress in neurons and could provide insight into neurological diseases associated with impaired Nedd4‐2 activity or an altered ER stress response.