Contents lists available at ScienceDirect BBA - Molecular and Cell Biology of Lipids journal homepage: www.elsevier.com/locate/bbalip Review Leading the way in the nervous system: Lipid Droplets as new players in health and disease Vitor Teixeira a,b, ⁎ , Patrícia Maciel c,d , Vítor Costa a,b,e a i3S - Instituto de Investigação e Inovação em Saúde, Universidade of Porto, Porto, Portugal b IBMC - Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal c Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal d ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal e ICBAS, Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal ARTICLEINFO Keywords: Lipid droplet Biogenesis Neuron Glia Motor neuron disease Neurodegeneration ABSTRACT Lipid droplets (LDs) are ubiquitous fat storage organelles composed of a neutral lipid core, comprising tria- cylglycerols (TAG) and sterol esters (SEs), surrounded by a phospholipid monolayer membrane with several decorating proteins. Recently, LD biology has come to the foreground of research due to their importance for energy homeostasis and cellular stress response. As aberrant LD accumulation and lipid depletion are hallmarks of numerous diseases, addressing LD biogenesis and turnover provides a new framework for understanding disease-related mechanisms. Here we discuss the potential role of LDs in neurodegeneration, while making some predictions on how LD imbalance can contribute to pathophysiology in the brain. https://doi.org/10.1016/j.bbalip.2020.158820 Received 8 June 2020; Received in revised form 1 September 2020; Accepted 21 September 2020 Abbreviations: Acsl, acyl-CoA synthetase long-chain; ACAT, acyl-coenzyme A:cholesterol acyltransferase; ACSL3, acyl-CoA synthetase long chain family member 3; AD, Alzheimer's disease; AGPAT, acylglycerol-3-phosphate acyltransferase; AIP, atrophin-1-interacting protein; ALS, amyotrophic lateral sclerosis; APO, apolipo- protein; ASC, apoptosis-associated speck-like protein containing a caspase recruitment domain; ATGL, adipose triglyceride lipase; ATL1, atlastin-1; ATP, adenosine triphosphate; BSCL2, Berardinelli-Seip congenital lipodystrophy 2; CARM1, coactivator-associated arginine methyltransferase 1; CDP-DAG, cytidyldiphosphate diacylglycerol; cAMP, cyclic adenosine monophosphate; CD36, cluster of diferentiation 36; CE, cholesterol ester; CMT, Charcot-Marie-Tooth disease; CNS, central nervous system; CPT, carnitine palmitoyltransferase; DAG, diacylglycerol; DDHD2, DDHD Domain Containing 2; DGAT, diacylglyceride acyltransferase; DGK, diacylglycerol kinase; dHMN, distal hereditary motor neuropathy; DIAPH1, diaphanous 1; DPR, dipeptide repeat; ER, endoplasmic reticulum; ESCRT, endosomal sorting complexes required for transport; FA, fatty acid; FATP, fatty acid transport protein; FFA, free fatty acid; FIT, fat storage-inducing transmembrane protein; FTD, frontotemporal dementia; G3P, glycerol-3-phosphate; GEF, guanine nucleotide exchange factor; Glaz, glial lazarillo; GPAT, glycerol-3-phosphate acyl- transferase; GTP, guanosine triphosphate; HEK293, human embryonic kidney 293; HILO, highly inclined and laminated optical sheet; HSL, hormone-sensitive lipase; HSP, hereditary spastic paraplegias; IFN, interferon; IL, interleukin; INM, inner nuclear membrane; JNK, c-Jun-N-terminal kinase; KB, ketone body; KCTD7, po- tassium channel tetramerization domain containing 7; KD, ketogenic diet; Klar, klarsicht; KO, knockout; LAL, lysosomal acid lipase; LC-PUFAs, long-chain poly- unsaturated fatty acids; LD, lipid droplet; LDAF1, lipid droplet assembly factor 1; LDAM, lipid-droplet-accumulating microglia; Ldh, lactate dehydrogenase; Ldo, LD organization; LPA, lysophosphatidic acid; MAG, monoacylglycerol; MAGL, monoacylglycerol lipase; MCP-1, monocyte chemoattractant protein 1; MCT, mono- carboxylate transporters; MCS, membrane contact sites; MIT, microtubule interaction and trafcking; MND, motor neuron disease; MSP, major sperm protein; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; NADPH, reduced nicotinamide adenine dinucleotide phosphate; NB, nuclear body; Nlaz, neural lazarillo; NLRP3, nucleotide-binding domain leucine-rich repeat (NLR) and pyrin domain containing receptor 3; NMDA, N-methyl-D-aspartate; NTE, neuropathy target esterase; NOX2, NADPH oxidase 2; NR, nucleoplasmic reticulum; ONM, outer nuclear membrane; PA, phosphatidic acid; PD, Parkinson's disease; Pdha, pyruvate dehydrogenase E1 component subunit alpha; PELD, progressive encephalopathy with or without lipodystrophy or Celia's encephalopathy; PKA, protein kinase A; PLD, phospholipase D; PLIN, perilipin; PML, premyelocytic leukemia; PX, Phox; RAGE, receptor for advanced glycation end products; REEP1, receptor expression-enhancing protein 1; RGS, regulator of G protein signalling; RNA, ribonucleic acid; ROS, reactive oxygen species; SCAR20, autosomal recessive spinocerebellar ataxia 20; SE, sterol ester; SMA, spinal muscular atrophy; SNX14, sorting nexin 14; SOCE, store-operated calcium entry; SOD1, superoxide dismutase 1; SPART, spartin; SPAST, spastin; SPG, spastic paraplegia; SPT, serine palmitoyltransferase; SREBP, sterol regulatory element binding protein; TAG, triacylglycerol; TCA, tricarboxylic acid cycle; VAMP, vesicle- associated membrane protein; hVAPB, human VAMP-associated protein B; WT, wild-type; WWP1, WW domain containing E3 ubiquitin protein ligase 1 ⁎ Corresponding author at: i3S - Instituto de Investigação e Inovação em Saúde, Universidade of Porto, Porto, Portugal. E-mail address: vitor.teixeira@ibmc.up.pt (V. Teixeira). BBA - Molecular and Cell Biology of Lipids 1866 (2021) 158820 Available online 01 October 2020 1388-1981/ © 2020 Elsevier B.V. All rights reserved. T