Deciphering lipid dysregulation in ALS: from mechanisms to translational medicine

Abstract

Lipids, defined by low solubility in water and high solubility in nonpolar solvents, can be classified into fatty acids, glycerolipids, glycerophospholipids, sphingolipids, and sterols. Lipids not only regulate integrity and fluidity of biological membranes, but also serve as energy storage and bioactive molecules for signaling. Causal mutations in SPTLC1 (serine palmitoyltransferase long chain subunit 1) gene within the lipogenic pathway have been identified in amyotrophic lateral sclerosis (ALS), a paralytic and fatal motor neuron disease. Furthermore, lipid dysmetabolism within the central nervous system and circulation is associated with ALS. Here, we aim to delineate the diverse roles of different lipid classes and understand how lipid dysmetabolism may contribute to ALS pathogenesis. Among the different lipids, accumulation of ceramides, arachidonic acid, and lysophosphatidylcholine is commonly emerging as detrimental to motor neurons. We end with exploring the potential ALS therapeutics by reducing these toxic lipids.

Keywords: Amyotrophic lateral sclerosis; Arachidonic acid; Ceramides; Cholesterol esters; Eicosanoids; Fatty acids; Lysophosphatidylcholine; Phospholipids; Sphingolipids; Triglycerides.

Fig. 1

Structural classification of lipids in biological systems. Presented here are the broad lipid classes of fatty acids, glycerolipids, glycerophospholipids, sphingolipids and sterols, and their main sub-classes, along with representative structures. Fatty acids (shown in blue) form the core of most lipid classes and are highly variable with differing chain lengths and saturation. Fatty acids with no double bonds, one double bond and multiple double bonds are further classified into saturated fatty acids, monounsaturated fatty acids, and polyunsaturated fatty acids, respectively. Glycerolipids are formed on addition of fatty acids to a glycerol backbone, while glycerophospholipids have additional phosphate and head groups added. Sphingolipids contain a sphingosine backbone attached with a fatty acid chain. Sterols are tetracyclic ring structures. Glycerol backbone, sphingosine backbone, phosphate group, glycerophospholipid head groups and sterol rings are colored orange, black, light green, purple, and dark green, respectively

Fig. 2

Representative structures of arachidonic acid-derived eicosanoid classes and associated inflammatory effects. Eicosanoids are derived from arachidonic acids, via either the 5-LOX-mediated pathway or COX-1/COX-2-mediated pathway. The 5-LOX-mediated pathway gives rise to eicosanoids such as leukotrienes and hydroxy-eicosatetraenoic acids, whereas the COX-1/COX-2-mediated pathway produces thromboxanes and prostaglandins. These eicosanoids are elevated in ALS disease states and exert pro-inflammatory effects. Endocannabinoids are synthesized reversibly from arachidonic acids. Arachidonoyl ethanolamide (AEA) and 2-arachidonoyl glycerol (2-AG) are endocannabinoids that are upregulated in ALS disease states. Binding and subsequent activation of AEA and 2-AG to CB1/CB2 receptors activates anti-inflammatory response

Fig. 3

Sphingolipid classes, metabolism, and associated diseases. Ceramides are the basic structural unit of sphingolipids, and can be synthesized de novo from palmitoyl coA, L-serine and fatty acyl coA with variable length (shown in blue), or from the breakdown of the more complex sphingolipid classes - glucosylceramides, galactosylceramides, lactosylceramides, gangliosides and sphingomyelin. Sphingosine-1-phosphate is the breakdown product of ceramide and is an active signaling molecule. Genetic variants of many of the key enzymes causing sphingolipid accumulation are causal for various neurodegenerative and metabolic diseases, including ALS and have been specified in the figure

Fig. 4

Potential therapeutic strategies targeting fatty acids. Upper panel shows an overview of fatty acid metabolism intervention points with neuroprotective effects. Fatty acids and derivatives shown to be toxic in ALS are highlighted in salmon pink. Lower panels describe the toxicity and the therapeutic strategies used in ALS mice and ALS patients. a Inhibition of the switch to fatty acid β-oxidation, b COX- and LOX-mediated arachidonic acid toxicity, and c CB1/CB2 receptor activation-mediated neuroprotection. Intervening compounds are in orange

Fig. 5

Ceramides and gangliosides therapeutic strategies. Upper panel shows an overview of sphingolipid metabolism intervention points. Sphingolipids with neurotoxic effects and neuroprotective effects in ALS conditions are highlighted in salmon pink and green, respectively. Lower panels describe the toxicity and the therapeutic strategies used. a Selective inhibition of SPTCL1 variant allele, b fingolimod-mediated neuroprotection, c inhibition of glucosylceramide breakdown, and d ganglioside-mediated therapeutics. Intervening compounds, RNAs and antibodies are highlighted in orange