Petratou, Dionysia et al. (2021) International Worm Meeting "The DEG/ΕNaC ion channel DEL-4 maintains neuronal ionstasis and promotes neuronal survival under stress"

Kaulich, Eva, Petratou, Dionysia, Gjikolaj, Martha, Schafer, William, Tavernarakis, Nektarios

[International Worm Meeting, 2021]

Physiological stress is sensed and processed by neurons, which initiate systemic stress responses. At the cellular level, ion homeostasis is of utmost importance for neuronal function, both for the maintenance of resting potential, and for the creation and propagation of action potentials. Indeed, imbalance in neuronal sodium homeostasis has been linked with many pathologies of the nervous system. However, the effects of stress on neuronal sodium homeostasis, excitability and survival are not understood. We find that DEL-4, an ENaC/DEG family member, which forms proton-inactivated homomeric sodium channels, is differentially regulated under stress to trigger appropriate cellular stress responses and motor adaptation. DEL-4 exhibits neuronal, non-synaptic localization and modulates the characteristics of Caenorhabditis elegans locomotory behavior. Heat stress and starvation alter DEL-4 expression, which in turn modulates the expression and activity of key stress response transcription factors, leading to increased autophagy and triggering of the ER stress response. Notably, similar to heat stress and starvation, DEL-4 deficiency causes hyperpolarization of dopaminergic neurons and impacts neurotransmission in dopaminergic and motor neurons. Utilizing two humanized models of Parkinson's and Alzheimer's disease in C. elegans, we show that DEL-4 promotes neuronal survival in the context of these proteinopathies. Our findings provide insight on the molecular mechanisms via which sodium channels uphold neuronal function and promote adaptation upon stress.