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.

SPTLC2 variants are associated with early‐onset ALS and FTD due to aberrant sphingolipid synthesis

“…Recent reports have linked SPTLC1 variants with early‐onset ALS 10,11 . Among these reports, some specifically highlighted elevated ceramide levels as a contributing factor, 10 a notion supported by observations of increased ceramide levels in the plasma and spinal cords of patients with SALS 12 . These findings emphasize the integral role of lipid metabolism disturbances in ALS pathogenesis.…”

Induced pluripotent stem cells‐based disease modeling, drug screening, clinical trials, and reverse translational research for amyotrophic lateral sclerosis

“…Recent studies have shown dysmetabolism of various lipid classes, such as fatty acids, glycerolipids, glycerophospholipids, sphingolipids, and sterols, in ALS patients (Agrawal et al., 2022; Liu et al., 2020; Nabizadeh et al., 2022). Lipids are believed to play a significant role in ALS pathogenesis and hold promise as both biomarkers and therapeutic targets.…”

“…Up until now, our research has primarily focused on studying cholesterol metabolism and lipid abnormalities in MNs as related to ALS. However, it is important to note that neurons themselves do not store lipid droplets; instead, they receive lipids from astrocytes' lipid droplets during energy‐demanding situations (Agrawal et al., 2022). This raises the possibility that abnormalities in lipid metabolism within glial cells (astrocytes, oligodendrocytes, and microglia) may play a role in the development of ALS.…”

“…Of note, Agrawal et al. (2022) highlighted that specific toxic lipids, such as ceramides and arachidonic acid, have particularly detrimental effects on MNs, while reducing their accumulation has shown beneficial results in various ALS models. In addition, increased levels of potentially beneficial lipids, such as glucosylceramides, and activation of S1P‐mediated signaling have been identified as potential protective factors in ALS.…”

Evidence for Alterations in Lipid Profiles and Biophysical Properties of Lipid Rafts From Spinal Cord in Amyotrophic Lateral Sclerosis

“…Multiple pathogenic mechanisms, including lipid dysregulation have been proposed to contribute to ALS (1,2,3,4). Indeed, dyslipidaemia and lipid dysregulation in the central nervous system and peripheral systems are prevalent in ALS patients, and have been reported to be clinically associated with disease severity, functional decline, and survival (3,4,5,6,7,8,9).…”