Emerging Links between Lipid Droplets and Motor Neuron Diseases

Lipid droplets (LDs) are ubiquitous fat storage organelles and play key roles in lipid metabolism and energy homeostasis; in addition, they contribute to protein storage, folding, and degradation. However, a role for LDs in the nervous system remains largely unexplored. We discuss evidence supporting an intimate functional connection between LDs and motor neuron disease (MND) pathophysiology, examining how LD functions in systemic energy homeostasis, in neuron-glia metabolic coupling, and in protein folding and clearance may affect or contribute to disease pathology. An integrated understanding of LD biology and neurodegeneration may open the way for new therapeutic interventions. Lipid droplets (LDs) are ubiquitous fat storage organelles and play key roles in lipid metabolism and energy homeostasis; in addition, they contribute to protein storage, folding, and degradation. However, a role for LDs in the nervous system remains largely unexplored. We discuss evidence supporting an intimate functional connection between LDs and motor neuron disease (MND) pathophysiology, examining how LD functions in systemic energy homeostasis, in neuron-glia metabolic coupling, and in protein folding and clearance may affect or contribute to disease pathology. An integrated understanding of LD biology and neurodegeneration may open the way for new therapeutic interventions. Motor neuron diseases (MNDs) are characterized by the gradual degeneration and death of motor neurons (MNs), resulting in progressive paralysis and muscle atrophy. Amyotrophic lateral sclerosis (ALS) is a fatal disease and the most common MND, with a worldwide annual incidence of ∼1.9 per 100,000 individuals (Arthur et al., 2016Arthur K.C. Calvo A. Price T.R. Geiger J.T. Chiò A. Traynor B.J. Projected increase in amyotrophic lateral sclerosis from 2015 to 2040.Nat. Commun. 2016; 7: 12408Crossref PubMed Scopus (215) Google Scholar). A plethora of genes with causative roles in ALS have been identified (Renton et al., 2014Renton A.E. Chiò A. Traynor B.J. State of play in amyotrophic lateral sclerosis genetics.Nat. Neurosci. 2014; 17: 17-23Crossref PubMed Scopus (1035) Google Scholar). Among the cellular processes implicated in ALS pathophysiology are ER stress and protein clearance, neuron-glia metabolic coupling, and energy homeostasis (Schmitt et al., 2014Schmitt F. Hussain G. Dupuis L. Loeffler J.P. Henriques A. A plural role for lipids in motor neuron diseases: energy, signaling and structure.Front. Cell. Neurosci. 2014; 8: 25Crossref PubMed Scopus (77) Google Scholar, Taylor et al., 2016Taylor J.P. Brown Jr., R.H. Cleveland D.W. Decoding ALS: from genes to mechanism.Nature. 2016; 539: 197-206Crossref PubMed Scopus (1093) Google Scholar). However, how alterations in these processes contribute to the disease remains poorly understood. Recently, connections have emerged between MNDs, including ALS, and lipid droplets (LDs), the cellular organelles for fat storage, possibly providing a new perspective for understanding disease-related mechanisms. LDs are ubiquitous organelles with a unique structure: a core of neutral lipids (triacylglycerols [TAGs] and sterol esters) surrounded by a monolayer of phospholipids and proteins. LDs originate from the ER, and, when lipids are needed, they are turned over by cytoplasmic lipases and autophagy. Mechanisms and regulation of LD biogenesis, growth, and turnover are active areas of investigation (Qi et al., 2017Qi Y. Sun L. Yang H. Lipid droplet growth and adipocyte development: mechanistically distinct processes connected by phospholipids.Biochim. Biophys. Acta. 2017; 1862: 1273-1283Crossref PubMed Scopus (21) Google Scholar, Schulze et al., 2017Schulze R.J. Sathyanarayan A. Mashek D.G. Breaking fat: The regulation and mechanisms of lipophagy.Biochim. Biophys. Acta. 2017; 1862: 1178-1187Crossref PubMed Scopus (133) Google Scholar, Walther et al., 2017Walther T.C. Chung J. Farese Jr., R.V. Lipid droplet biogenesis.Annu. Rev. Cell Dev. Biol. 2017; 33: 491-510Crossref PubMed Scopus (342) Google Scholar). LDs play critical roles in cellular processes also implicated in ALS pathophysiology. Foremost is their role in energy homeostasis, because they provide fatty acid (FA) fuel for ATP production. Emerging evidence also links LDs to neuron-glia metabolic coupling (Liu et al., 2017Liu L. MacKenzie K.R. Putluri N. Maletić-Savatić M. Bellen H.J. The glia-neuron lactate shuttle and elevated ROS promote lipid synthesis in neurons and lipid droplet accumulation in glia via APOE/D.Cell Metab. 2017; 26: 719-737.e6Abstract Full Text Full Text PDF PubMed Scopus (210) Google Scholar). Furthermore, LDs are involved in the resolution of ER stress and the clearing of protein aggregates (Welte, 2015Welte M.A. Expanding roles for lipid droplets.Curr. Biol. 2015; 25: R470-R481Abstract Full Text Full Text PDF PubMed Scopus (318) Google Scholar, Welte and Gould, 2017Welte M.A. Gould A.P. Lipid droplet functions beyond energy storage.Biochim. Biophys. Acta. 2017; 1862: 1260-1272Crossref PubMed Scopus (271) Google Scholar). Genetic studies suggest that this overlap between LD functions and cellular processes implicated in ALS is not mere happenstance: many genes responsible for ALS, as well as for the MND hereditary spastic paraplegia (HSP), play important roles in LD biology; on the other hand, disruption of lipid metabolism and energy homeostasis are prevalent in ALS (see below; Schmitt et al., 2014Schmitt F. Hussain G. Dupuis L. Loeffler J.P. Henriques A. A plural role for lipids in motor neuron diseases: energy, signaling and structure.Front. Cell. Neurosci. 2014; 8: 25Crossref PubMed Scopus (77) Google Scholar). Here we discuss the role of LDs in energy homeostasis, glia-neuron metabolic coupling, and protein aggregation and clearance, and we formulate mechanistic hypotheses on how disruption of these LD-mediated processes could contribute to ALS pathophysiology. Although additional studies are needed to assess the specific role of LDs in ALS and other MNDs, it is conceivable that targeting LD-related processes might lead to new therapies for these devastating diseases. Neurons have extremely high energy demands, and LDs are crucial for energy homeostasis in most cells. Might LD dysfunction promote neurodegeneration by disrupting the energy metabolism of neurons? At first glance, such a scenario seems unlikely because neurons derive much of their energy from glucose. However, when glucose is limiting, neurons use energy-rich substrates ultimately derived from the breakdown of FAs. Below, we discuss how LDs in various tissues across the organism could metabolically support MNs. We then contrast this systemic role with a local function in which LDs in glia provide fuel for neighboring neurons. Finally, we consider whether LD functions beyond energy metabolism could directly affect MNs. The brain lacks fuel stores and relies on a continuous supply of glucose from peripheral organs, especially the liver. When glucose is scarce, the liver coverts Acetyl-CoA produced during FA β oxidation into ketone bodies (KBs). KBs are transported through the bloodstream to the brain, where they are oxidized to produce energy. FAs metabolized in the liver are, in turn, replenished from dietary lipids in the gut or from lipids stored in adipose tissue. In all of these tissues, FAs are stored as TAGs in LDs; thus, LD dysfunction could indirectly impact MNs. This notion is attractive because many ALS genes are ubiquitously expressed, and non-cell-autonomous processes can contribute to neuronal damage in ALS (Ilieva et al., 2009Ilieva H. Polymenidou M. Cleveland D.W. Non-cell autonomous toxicity in neurodegenerative disorders: ALS and beyond.J. Cell Biol. 2009; 187: 761-772Crossref PubMed Scopus (788) Google Scholar). A link between ALS and disrupted organismal lipid metabolism is suggested by emerging data on TDP-43, a ubiquitous protein encoded by the ALS10 gene. TDP-43-mediated ALS may be caused by loss of its normal function, gain of new toxic functions, or possibly a combination of both (Polymenidou and Cleveland, 2017Polymenidou M. Cleveland D.W. Biological spectrum of amyotrophic lateral sclerosis prions.Cold Spring Harb. Perspect. Med. 2017; 7: a024133Crossref PubMed Scopus (17) Google Scholar, Robberecht and Philips, 2013Robberecht W. Philips T. The changing scene of amyotrophic lateral sclerosis.Nat. Rev. Neurosci. 2013; 14: 248-264Crossref PubMed Scopus (717) Google Scholar). TDP-43-overexpressing mice display neurological symptoms, motor deficits, increased fat accumulation, and adipocyte hypertrophy (Stallings et al., 2013Stallings N.R. Puttaparthi K. Dowling K.J. Luther C.M. Burns D.K. Davis K. Elliott J.L. TDP-43, an ALS linked protein, regulates fat deposition and glucose homeostasis.PLoS One. 2013; 8: e71793Crossref PubMed Scopus (63) Google Scholar). Depleting TDP-43 postnatally in mice causes weight loss, body fat reduction, decreased adipocyte LD content, increased FA consumption, and rapid death (Chiang et al., 2010Chiang P.M. Ling J. Jeong Y.H. Price D.L. Aja S.M. Wong P.C. Deletion of TDP-43 down-regulates Tbc1d1, a gene linked to obesity, and alters body fat metabolism.Proc. Natl. Acad. Sci. USA. 2010; 107: 16320-16324Crossref PubMed Scopus (216) Google Scholar). What is the mechanistic basis for these profound physiological changes? In skeletal muscles, TDP-43 depletion blocks insulin-induced trafficking of the glucose transporter Glut4 to the plasma membrane by downregulating the Rab-GTPase-activating protein TBC1D1. Consequently, impairment in glucose uptake induces a metabolic switch toward lipids for energy production. Elevated FA consumption and oxidation by skeletal muscles presumably explain increased fat mobilization from adipose tissue (Chadt et al., 2008Chadt A. Leicht K. Deshmukh A. Jiang L.Q. Scherneck S. Bernhardt U. Dreja T. Vogel H. Schmolz K. Kluge R. et al.Tbc1d1 mutation in lean mouse strain confers leanness and protects from diet-induced obesity.Nat. Genet. 2008; 40: 1354-1359Crossref PubMed Scopus (165) Google Scholar, Chiang et al., 2010Chiang P.M. Ling J. Jeong Y.H. Price D.L. Aja S.M. Wong P.C. Deletion of TDP-43 down-regulates Tbc1d1, a gene linked to obesity, and alters body fat metabolism.Proc. Natl. Acad. Sci. USA. 2010; 107: 16320-16324Crossref PubMed Scopus (216) Google Scholar). We speculate that TBC1D1 might even affect fat storage directly, because the related isoform AS160/TBC1D4 regulates both Glut4 translocation and LD growth in adipocytes (Wu et al., 2014Wu L. Xu D. Zhou L. Xie B. Yu L. Yang H. Huang L. Ye J. Deng H. Yuan Y.A. et al.Rab8a-AS160-MSS4 regulatory circuit controls lipid droplet fusion and growth.Dev. Cell. 2014; 30: 378-393Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar). In a yeast model for ALS, TDP-43 toxicity is enhanced by depletion of seipin (Armakola et al., 2012Armakola M. Higgins M.J. Figley M.D. Barmada S.J. Scarborough E.A. Diaz Z. Fang X. Shorter J. Krogan N.J. Finkbeiner S. et al.Inhibition of RNA lariat debranching enzyme suppresses TDP-43 toxicity in ALS disease models.Nat. Genet. 2012; 44: 1302-1309Crossref PubMed Scopus (182) Google Scholar). Seipin has a prominent role in LD biogenesis and growth and is the causative gene of two MN disorders: distal hereditary motor neuropathy type V (dHMN-V) and Silver syndrome (Welte, 2015Welte M.A. Expanding roles for lipid droplets.Curr. Biol. 2015; 25: R470-R481Abstract Full Text Full Text PDF PubMed Scopus (318) Google Scholar). Intriguingly, the hVAPB/ALS8 gene also controls Glut4 trafficking, both in myoblasts and adipocytes, and affects LD size, number, and composition (Al-Anzi et al., 2015Al-Anzi B. Arpp P. Gerges S. Ormerod C. Olsman N. Zinn K. Experimental and computational analysis of a large protein network that controls fat storage reveals thse design principles of a signaling network.PLoS Comput. Biol. 2015; 11: e1004264Crossref PubMed Scopus (6) Google Scholar, Foster et al., 2000Foster L.J. Weir M.L. Lim D.Y. Liu Z. Trimble W.S. Klip A. A functional role for VAP-33 in insulin-stimulated GLUT4 traffic.Traffic. 2000; 1: 512-521Crossref PubMed Scopus (69) Google Scholar, Jansen et al., 2011Jansen M. Ohsaki Y. Rega L.R. Bittman R. Olkkonen V.M. Ikonen E. Role of ORPs in sterol transport from plasma membrane to ER and lipid droplets in mammalian cells.Traffic. 2011; 12: 218-231Crossref PubMed Scopus (76) Google Scholar). Mutations in genes controlling LD biogenesis and dynamics modify ALS8 phenotypes in flies (Sanhueza et al., 2015Sanhueza M. Chai A. Smith C. McCray B.A. Simpson T.I. Taylor J.P. Pennetta G. Network analyses reveal novel aspects of ALS pathogenesis.PLoS Genet. 2015; 11: e1005107Crossref PubMed Scopus (38) Google Scholar), and in C. elegans and mice, VAPB depletion induces LD accumulation and clustering in muscles (Han et al., 2013Han S.M. El Oussini H. Scekic-Zahirovic J. Vibbert J. Cottee P. Prasain J.K. Bellen H.J. Dupuis L. Miller M.A. VAPB/ALS8 MSP ligands regulate striated muscle energy metabolism critical for adult survival in caenorhabditis elegans.PLoS Genet. 2013; 9: e1003738Crossref PubMed Scopus (29) Google Scholar). In humans, mutations in spatacsin cause ALS and the MND HSP11, and its loss in mice induces MN degeneration, muscle atrophy, and a decrease in the steady-state number of LDs, possibly due to defective clearance of lipids by lysosomes (Branchu et al., 2017Branchu J. Boutry M. Sourd L. Depp M. Leone C. Corriger A. Vallucci M. Esteves T. Matusiak R. Dumont M. et al.Loss of spatacsin function alters lysosomal lipid clearance leading to upper and lower motor neuron degeneration.Neurobiol. Dis. 2017; 102: 21-37Crossref PubMed Scopus (59) Google Scholar). Evidence pointing to a metabolic switch from glucose toward lipids is also emerging in SOD1 mouse models of ALS: their spinal cord neurons display decreased glucose usage (Miyazaki et al., 2012Miyazaki K. Masamoto K. Morimoto N. Kurata T. Mimoto T. Obata T. Kanno I. Abe K. Early and progressive impairment of spinal blood flow-glucose metabolism coupling in motor neuron degeneration of ALS model mice.J. Cereb. Blood Flow Metab. 2012; 32: 456-467Crossref PubMed Scopus (55) Google Scholar), and a fat-rich diet restores normal body mass, delays disease onset and MN degeneration, and extends life expectancy (Schmitt et al., 2014Schmitt F. Hussain G. Dupuis L. Loeffler J.P. Henriques A. A plural role for lipids in motor neuron diseases: energy, signaling and structure.Front. Cell. Neurosci. 2014; 8: 25Crossref PubMed Scopus (77) Google Scholar). Consistent with a change in fuel preference in SOD1 mice, denervation of glycolytic muscle fibers, an early pre-symptomatic event, is preceded by increased expression of lipid-handling genes (Palamiuc et al., 2015Palamiuc L. Schlagowski A. Ngo S.T. Vernay A. Dirrig-Grosch S. Henriques A. Boutillier A.L. Zoll J. Echaniz-Laguna A. Loeffler J.P. René F. A metabolic switch toward lipid use in glycolytic muscle is an early pathologic event in a mouse model of amyotrophic lateral sclerosis.EMBO Mol. Med. 2015; 7: 526-546Crossref PubMed Scopus (135) Google Scholar). Increased FA requirements may explain why hyperlipidaemia positively correlates with survival in ALS patients and why they exhibit enhanced circulating levels of KBs (Schmitt et al., 2014Schmitt F. Hussain G. Dupuis L. Loeffler J.P. Henriques A. A plural role for lipids in motor neuron diseases: energy, signaling and structure.Front. Cell. Neurosci. 2014; 8: 25Crossref PubMed Scopus (77) Google Scholar). Collectively, emerging evidence links ALS to systemic disruption of lipid metabolism (Figure 1A), though it remains to be established whether LD defects contribute to disease pathology or play more direct causative roles. We propose that LD dysfunction in various peripheral organs could throttle energy delivery to neurons and muscles, an energy supply these cells depend on under disease conditions. Neurons also derive fuel substrates from glia. According to the astrocyte-neuron lactate shuttle hypothesis, under conditions of intense neuronal activity, astrocytes—a type of glia—deliver glucose-derived lactate to neurons for ATP production (Bélanger et al., 2011Bélanger M. Allaman I. Magistretti P.J. Brain energy metabolism: focus on astrocyte-neuron metabolic cooperation.Cell Metab. 2011; 14: 724-738Abstract Full Text Full Text PDF PubMed Scopus (1338) Google Scholar). Neurons can also receive lactate from oligodendrocytes (glial cells in the CNS that myelinate axons) via monocarboxylate transporters (MCTs). MCT1 ablation leads to axon damage and neuronal degeneration, and MCT1 levels are reduced in affected brain regions from ALS patients and in SOD1 mouse models of ALS (Lee et al., 2012Lee Y. Morrison B.M. Li Y. Lengacher S. Farah M.H. Hoffman P.N. Liu Y. Tsingalia A. Jin L. Zhang P.W. et al.Oligodendroglia metabolically support axons and contribute to neurodegeneration.Nature. 2012; 487: 443-448Crossref PubMed Scopus (1046) Google Scholar). Intriguingly, MCTs can also transport KBs (Halestrap, 2012Halestrap A.P. The monocarboxylate transporter family--Structure and functional characterization.IUBMB Life. 2012; 64: 1-9Crossref PubMed Scopus (440) Google Scholar), and emerging evidence suggests that glia provide KBs as fuel to neurons, suggesting a link between LDs and ALS. KBs are largely supplied by the liver; but, like hepatocytes, astrocytes use FAs as primary metabolic fuel and produce large amounts of KBs using a ketogenic machinery that is similar in both cell types (Guzmán and Blázquez, 2001Guzmán M. Blázquez C. Is there an astrocyte-neuron ketone body shuttle?.Trends Endocrinol. Metab. 2001; 12: 169-173Abstract Full Text Full Text PDF PubMed Scopus (157) Google Scholar). This machinery requires the sequential action of three enzymes to transport FAs from the cytosol to the mitochondrial matrix. CPT1 (carnitine-palmitoyltransferase1) on the outer mitochondrial membrane conjugates carnitine with FAs; CACT (carnitine-acylcarnitine translocase) transfers acylcarnitine across the inner mitochondrial membrane where CPT2 conjugates FAs back to Coenzyme-A for subsequent β oxidation. Inside mitochondria, acetyl moieties condense to generate KBs. In vivo, loss of CPT2 leads to increased starvation sensitivity and reduced lifespan of Drosophila adults. Because these phenotypes are reversed by selectively restoring CPT2 expression in glia, it was proposed that KB production and release from glia help power the brain (Schulz et al., 2015Schulz J.G. Laranjeira A. Van Huffel L. Gärtner A. Vilain S. Bastianen J. Van Veldhoven P.P. Dotti C.G. Glial β-oxidation regulates Drosophila energy metabolism.Sci. Rep. 2015; 5: 7805Crossref PubMed Scopus (41) Google Scholar). Together, these observations support a model in which disruption of KB production from LD-derived lipids or of their delivery may impact energy-dependent processes important for MN function and survival (Figure 1B). Consistent with this idea, inactivation of CTP2 in Drosophila leads to selective accumulation of LDs in glia, and glia-specific CPT2 expression reverses this phenotype (Schulz et al., 2015Schulz J.G. Laranjeira A. Van Huffel L. Gärtner A. Vilain S. Bastianen J. Van Veldhoven P.P. Dotti C.G. Glial β-oxidation regulates Drosophila energy metabolism.Sci. Rep. 2015; 5: 7805Crossref PubMed Scopus (41) Google Scholar). Although it used to be controversial whether neuronal LDs exist at all, they have now been clearly identified in axons of Aplysia (Savage et al., 1987Savage M.J. Goldberg D.J. Schacher S. 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Orso G. Mancuso G. Herholz M. Gumeni S. Tadepalle N. Jüngst C. Tzschichholz A. Schauss A. Höning S. et al.Spastin binds to lipid droplets and affects lipid metabolism.PLoS Genet. 2015; 11: e1005149Crossref PubMed Scopus (70) Google Scholar), and neuroblastoma cell lines (Hölttä-Vuori et al., 2013Hölttä-Vuori M. Salo V.T. Ohsaki Y. Suster M.L. Ikonen E. Alleviation of seipinopathy-related ER stress by triglyceride storage.Hum. Mol. Genet. 2013; 22: 1157-1166Crossref PubMed Scopus (31) Google Scholar). Presence and abundance of neuronal LDs vary tremendously and may depend on variables such as developmental stage, nutrient conditions, or environmental conditions. In Drosophila glia, for example, LDs are induced by hypoxia in larvae (Bailey et al., 2015Bailey A.P. Koster G. Guillermier C. Hirst E.M. MacRae J.I. Lechene C.P. Postle A.D. Gould A.P. Antioxidant role for lipid droplets in a stem cell niche of drosophila.Cell. 2015; 163: 340-353Abstract Full Text Full Text PDF PubMed Scopus (300) Google Scholar) and by neurodegeneration in adults (Liu et al., 2015Liu L. Zhang K. Sandoval H. Yamamoto S. Jaiswal M. Sanz E. Li Z. Hui J. Graham B.H. Quintana A. Bellen H.J. Glial lipid droplets and ROS induced by mitochondrial defects promote neurodegeneration.Cell. 2015; 160: 177-190Abstract Full Text Full Text PDF PubMed Scopus (425) Google Scholar). Sex-related differences in FA metabolism (Bakewell et al., 2006Bakewell L. Burdge G.C. Calder P.C. Polyunsaturated fatty acid concentrations in young men and women consuming their habitual diets.Br. J. Nutr. 2006; 96: 93-99Crossref PubMed Scopus (128) Google Scholar, Hoyenga and Hoyenga, 1982Hoyenga K.B. Hoyenga K.T. Gender and energy balance: sex differences in adaptations for feast and famine.Physiol. Behav. 1982; 28: 545-563Crossref PubMed Scopus (88) Google Scholar) could explain why cultured neurons isolated from females accumulate more LDs than neurons from males (Du et al., 2009Du L. Hickey R.W. Bayir H. Watkins S.C. Tyurin V.A. Guo F. Kochanek P.M. Jenkins L.W. Ren J. Gibson G. et al.Starving neurons show sex difference in autophagy.J. Biol. Chem. 2009; 284: 2383-2396Crossref PubMed Scopus (159) Google Scholar). Neuronal LDs may also be rare or transient, making their identification particularly challenging. In the adult mouse brain, LDs are rarely found, but they accumulate prominently inside neurons when their turnover is impaired by mutations in the TAG hydrolase DDHD2 (Inloes et al., 2014Inloes J.M. Hsu K.L. Dix M.M. Viader A. Masuda K. Takei T. Wood M.R. Cravatt B.F. The hereditary spastic paraplegia-related enzyme DDHD2 is a principal brain triglyceride lipase.Proc. Natl. Acad. Sci. USA. 2014; 111: 14924-14929Crossref PubMed Scopus (96) Google Scholar). DDHD2 mouse knockouts exhibit motor and cognitive dysfunctions with extensive neurodegeneration, and in humans, DDHD2 mutations cause a MND known as HSP54 (Inloes et al., 2014Inloes J.M. Hsu K.L. Dix M.M. Viader A. Masuda K. Takei T. Wood M.R. Cravatt B.F. The hereditary spastic paraplegia-related enzyme DDHD2 is a principal brain triglyceride lipase.Proc. Natl. Acad. Sci. USA. 2014; 111: 14924-14929Crossref PubMed Scopus (96) Google Scholar). DDHD2-depleted neurons exhibit swelling of axons and dendrites, and Drosophila neuromuscular junctions lacking DDHD2 display fewer active zones, the sites of neurotransmitter release (Schuurs-Hoeijmakers et al., 2012Schuurs-Hoeijmakers J.H. Geraghty M.T. Kamsteeg E.J. Ben-Salem S. de Bot S.T. Nijhof B. van de Vondervoort I.I. van der Graaf M. Nobau A.C. Otte-Höller I. et al.FORGE Canada ConsortiumMutations in DDHD2, encoding an intracellular phospholipase A(1), cause a recessive form of complex hereditary spastic paraplegia.Am. J. Hum. Genet. 2012; 91: 1073-1081Abstract Full Text Full Text PDF PubMed Scopus (124) Google Scholar). We therefore speculate that excessive LDs may sequester and disrupt the trafficking of proteins and lipids required for synapse assembly. Indeed, LDs from mutant brains are associated with several proteins implicated in neuronal function (Figure 2) (Inloes et al., 2018Inloes J.M. Kiosses W.B. Wang H. Walther T.C. Farese Jr., R.V. Cravatt B.F. Functional contribution of the spastic paraplegia-related triglyceride hydrolase DDHD2 to the formation and content of lipid droplets.Biochemistry. 2018; 57: 827-838Crossref PubMed Scopus (27) Google Scholar). Conversely, LDs in glia are larger and more easily detected than in neurons. Heterogeneity in LD content across a cell population was proposed to promote metabolic specialization. In the liver, some cells accumulate more LDs than their neighbors and, when needed, efficiently deliver FAs to surrounding cells (Herms et al., 2013Herms A. Bosch M. Ariotti N. Reddy B.J. Fajardo A. Fernández-Vidal A. Alvarez-Guaita A. Fernández-Rojo M.A. Rentero C. Tebar F. et al.Cell-to-cell heterogeneity in lipid droplets suggests a mechanism to reduce lipotoxicity.Curr. Biol. 2013; 23: 1489-1496Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar). This heterogeneity may represent a strategy to alleviate the overall risk of lipotoxicity, because cells with high LD content and higher levels of reactive oxygen species (ROS) express specialized defense mechanisms against oxidative damage. Might a similar division of labor also exist within the brain, with glia as the high-lipid content cells? Intriguingly, astrocytes contain higher levels of anti-oxidant molecules and ROS-detoxifying enzymes than neurons (Bélanger et al., 2011Bélanger M. Allaman I. Magistretti P.J. Brain energy metabolism: focus on astrocyte-neuron metabolic cooperation.Cell Metab. 2011; 14: 724-738Abstract Full Text Full Text PDF PubMed Scopus (1338) Google Scholar). There is direct evidence that LDs in glia protect neighboring neurons from oxidative stress (Figure 1B). In Drosophila adults and in mice, mitochondrial dysfunction promotes—via ROS accumulation—increased synthesis of lipids, which are then transferred from neurons to glia and stored in LDs (Liu et al., 2015Liu L. Zhang K. Sandoval H. Yamamoto S. Jaiswal M. Sanz E. Li Z. Hui J. Graham B.H. Quintana A. Bellen H.J. Glial lipid droplets and ROS induced by mitochondrial defects promote neurodegeneration.Cell. 2015; 160: 177-190Abstract Full Text Full Text PDF PubMed Scopus (425) Google Scholar, Liu et al., 2017Liu L. MacKenzie K.R. Putluri N. Maletić-Savatić M. Bellen H.J. The glia-neuron lactate shuttle and elevated ROS promote lipid synthesis in neurons and lipid droplet accumulation in glia via APOE/D.Cell Metab. 2017; 26: 719-737.e6Abstract Full Text Full Text PDF PubMed Scopus (210) Google Scholar). In Drosophila larvae, increased glial LD content due to ROS accumulation (e.g., under hypoxia conditions) is protective, because if glia are unable to make LDs, neurons exhibit increased damage from peroxidation (Bailey et al., 2015Bailey A.P. Koster G. Guillermier C. Hirst E.M. MacRae J.I. Lechene C.P. Postle A.D. Gould A.P. Antioxidant role for lipid droplets in a stem cell niche of drosophila.Cell. 2015; 163: 340-353Abstract Full Text Full Text PDF PubMed Scopus (300) Google Scholar). It was proposed that glial LDs sequester lipids away from the plasma membrane, especially lipids containing polyunsaturated FAs (PUFAs), which are particularly vulnerable to peroxidation by ROS. PUFAs are more protected when incorporated into TAGs within LDs than when they are in phospholipids of cell membranes. During ROS-induced apoptosis, PUFAs of membrane phospholipids are peroxidated, whereas their incorporation into LDs is thought to decrease their toxicity, suggesting that protection from oxidative stress is a general role of LDs (Li et al., 2018Li N. Sancak Y. Frasor J. Atilla-Gokcumen G.E. A protective role for triacylglycerols during apoptosis.Biochemistry. 2018; 57: 72-80Crossref PubMed Scopus (29) Google Scholar). This protective role could be relevant for ALS because oxidative stress due to mitochondrial dysfunction is a leading cause of MN injury in ALS (Barber and Shaw, 2010Barber S.C. Shaw P.J. Oxidative stress in ALS: key role in motor neuron injury and therapeutic target.Free Radic. Biol. Med. 2010; 48: 629-641Crossref PubMed Scopus (433) Google Scholar). Consistently, markers of lipid peroxidation are found in the cerebrospinal fluid of ALS patients and in disease models, suggesting that accumulation of these toxic molecules might contribute to ALS (Simpson et al., 2004Simpson E.P. Henry Y.K. Henkel J.S. Smith R.G. Appel S.H. Increased lipid peroxidation in sera of ALS patients: a potential biomarker of disease burden.Neurology. 2004; 62: 1758-1765Crossref PubMed Scopus (249) Google Scholar, Smith et al., 1998Smith R.G. Henry Y.K. Mattson M.P. Appel S.H. Presence of 4-hydroxynonenal in cerebrospinal fluid of patients with sporadic amyotrophic lateral sclerosis.Ann. Neurol. 1998; 44: 696-699Crossref PubMed Scopus (199) Google Scholar). Protein turnover is critical for ALS, because a number of ALS-linked mutations affect genes directly involved in protein clearance and homeostasis (Taylor et al., 2016Taylor J.P. Brown Jr., R.H. Cleveland D.W. Decoding ALS: from genes to mechanism.Nature. 2016; 539: 197-206Crossref PubMed Scopus (1093) Google Scholar). Emerging evidence also suggests that LDs play a fundamental role in protein aggregation and clearance. Below, we discuss whether