GABA signaling triggered by TMC-1/Tmc delays neuronal aging by inhibiting the PKC pathway in C. elegans

Aging causes functional decline and degeneration of neurons and is a major risk factor of neurodegenerative diseases. To investigate the molecular mechanisms underlying neuronal aging, we developed a new pipeline for neuronal proteomic profiling in young and aged animals. While the overall translational machinery is downregulated, certain proteins increase expressions upon aging. Among these aging- up-regulated proteins, the conserved channel protein TMC-1/Tmc has an anti-aging function in all neurons tested, and the neuroprotective function of TMC-1 occurs by regulating GABA signaling. Moreover, our results show that metabotropic GABA receptors and G protein GOA-1/Goa are required for the anti-neuronal aging functions of TMC-1 and GABA, and the activation of GABA receptors prevents neuronal aging by inhibiting the PLC ss-PKC pathway. Last, we show that the TMC-1-GABA- PKC signaling axis suppresses neuronal functional decline caused by a pathogenic form of human Tau protein. Together, our findings reveal the neuroprotective function of the TMC-1-GABA- PKC signaling axis in aging and disease conditions.

Automated summary

Aging is a major risk factor for neurodegenerative diseases, leading to functional decline and degeneration of neurons. Through a new method of neuronal proteomic profiling, certain proteins, including TMC-1, were found to have increased expression levels during aging, and TMC-1 was shown to have an anti-aging function in all tested neurons by regulating GABA signaling. Furthermore, the study demonstrated the vital role of metabotropic GABA receptors and G protein GOA-1 in the anti-neuronal aging functions of TMC-1 and GABA, and the activation of GABA receptors prevents neuronal aging by inhibiting the PLC ss-PKC pathway.