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However, the pathological connection between lipid droplets and NDs remains poorly understood. The recent work has highlighted the utility of a neuron\u2010specific Arf1\u2010knockout mouse model and corresponding cells for elucidating the nexus between lipid metabolism disorders and amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS). In this study, it is found that Arf1 deficiency first induced surplus fatty acid synthesis through the AKT\u2010mTORC1\u2010SREBP1\u2010FASN axis, which further triggered endoplasmic reticulum (ER)\u2010mitochondrial stress cascade via calcium flux. The organelle stress cascade further caused mitochondrial DNA (mtDNA) to be released into cytoplasm. Concurrently, the FASN\u2010driven fatty acid synthesis in the Arf1\u2010deficient neurons might also induce accumulation of sphingolipids in lysosomes that caused dysfunction of autophagy and lysosomes, which further promoted lysosomal stress and mitochondria\u2010derived extracellular vesicles (MDEVs)\u00a0release. The released MDEVs carried mtDNA into microglia to activate the inflammatory pathways and neurodegeneration. The studies on neuronal lipid droplets (LDs) and recent studies of microglial LDs suggest a unified pathological function of LDs in NDs: activating the inflammatory pathways in microglia. This finding potentially provides new therapeutic strategies for NDs.<\/jats:p>","DOI":"10.1002\/advs.202414260","type":"journal-article","created":{"date-parts":[[2025,3,12]],"date-time":"2025-03-12T05:36:36Z","timestamp":1741757796000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Accumulation of Damaging Lipids in the Arf1\u2010Ablated Neurons Promotes Neurodegeneration through Releasing mtDNA and Activating Inflammatory Pathways in Microglia"],"prefix":"10.1002","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-1013-0208","authenticated-orcid":false,"given":"Xu","family":"Li","sequence":"first","affiliation":[{"name":"Department of Cell and Developmental Biology at School of Life Sciences State Key Laboratory of Genetic Engineering Institute of Metabolism and Integrative Biology Children's Hospital Zhongshan Hospital Fudan University  Shanghai 200438 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