Neuronal lipolysis participates in PUFA-mediated neural function and neurodegeneration

Abstract

Lipid droplets (LDs) are dynamic cytoplasmic organelles present in most eukaryotic cells. The appearance of LDs in neurons is not usually observed under physiological conditions, but is associated with neural diseases. It remains unclear how LD dynamics is regulated in neurons and how the appearance of LDs affects neuronal functions. We discovered that mutations of two key lipolysis genes atgl-1 and lid-1 lead to LD appearance in neurons of Caenorhabditis elegans. This neuronal lipid accumulation protects neurons from hyperactivation-triggered neurodegeneration, with a mild decrease in touch sensation. We also discovered that reduced biosynthesis of polyunsaturated fatty acids (PUFAs) causes similar effects, synergistically with decreased lipolysis. Furthermore, we demonstrated that these changes in lipolysis and PUFA biosynthesis increase PUFA partitioning toward triacylglycerol, and reduced incorporation of PUFAs into phospholipids increases neuronal protection. Together, these results suggest the crucial role of neuronal lipolysis in regulating neural functions and neurodegeneration cell-autonomously. HighlightsO_LINeuronal lipolysis prevents LD accumulation in neurons. C_LIO_LIDefective neuronal lipolysis leads to touch sensation defect. C_LIO_LIBlocking neuronal lipolysis alleviates neurodegeneration. C_LIO_LINeuronal lipolysis and de novo PUFA biosynthesis have a synergistic effect in neurodegeneration. C_LIO_LIThe incorporation of PUFAs into phospholipids promotes neurodegeneration. C_LI