Glial ceramide orchestrates lipid homeostasis and age-dependent motor function.

Glial cells have emerged as equal partners to neurons in the development and maintenance of the nervous system. In this study, we examine the consequences of modulating glial ceramide metabolism on adult motor function. Glial reduction of ER-localised ceramide synthesis, as exemplified by knockdown (KD) of schlank or ifc or lace, leads to age-dependent motor defects, as does KD of ceramide transfer protein (CERT). Motor defects in CERT-null animals can be significantly rescued by glial CERT expression, further highlighting the importance of glial ceramide homeostasis. Expectedly, glial schlank KD and CERT KD lead to lipid modulation in the brain, characterised by decreased ceramide phosphoethanolamine, increased ceramide phosphates and triacylglycerols, as measured by lipid mass spectrometry, and intriguingly, decreased Lipid Droplet (LD) size and density. Further, disruption of CERT's interaction with the ER-tethering protein VAPB also affects LD dynamics. Our research implicates the glial sphingolipid pathway as an important determinant of age-dependent adult motor function, with LDs serving as a sensitive diagnostic readout. As such, our study has implications for a host of human motor neuron diseases with late-onset motor deficits.