Arf1-deficiency-induced neuronal surplus fatty acid synthesis evokes neurodegeneration through mtDNA releasing and inflammatory activating in microglia

The crucial role of lipid metabolism disorders and neuronal inflammation has been revealed in many studies of neurodegenerative diseases. However, the pathological connection between lipid droplets and neuronal immune circuits remains poorly understood. We have previously reported a neuronal-specific Arf1-knockout mouse as an ideal lipid metabolism disorder-induced neurodegeneration model. Here, we found that Arf1-deficiency first induced surplus fatty acid synthesis and lipid droplets (LDs) accumulation through the AKT-mTORC1-SREBP1-FASN axis, which further triggered endoplasmic reticulum (ER)-mitochondrial stress cascade via calcium flux. The organelle stress cascade further induced mitochondrial DNA (mtDNA) to be released into the cytoplasm. Meanwhile, the FASN-driven fatty acid synthesis in the Arf1-deficient neurons also induced lysosomal sphingolipids accumulation that caused dysfunction of autophagy and lysosomes, which enables the neuronal mtDNA to transfer to microglia via extracellular vesicles (EVs) and activates the inflammatory pathways to aggravate neurodegeneration. Furthermore, inhibition of FASN or boosting autophagy in vivo reversed neuronal degeneration disease in Arf1-knockout mice. Our study suggests a unified pathological function of LD in NDs and proves that inhibition of fatty acid synthesis-induced inflammation might be a therapeutic route to neuronal degeneration disease.