Neutral lipid cacostasis contributes to disease pathogenesis in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a fatal neuromuscular disease characterized by motor neuron (MN) death. Lipid dysregulation manifests during disease; however, it is unclear if lipid homeostasis is adversely affected in the in the spinal cord (SC) grey matter (GM), and if so, whether it is due to an aberrant increase in lipid synthesis. Moreover, it is unknown if lipid dysregulation contributes to MN death. Here, we show that cholesterol ester (CE) and triacylglycerol (TAG) levels are elevated several-fold in the SC GM of male sporadic ALS patients. Interestingly, HMG-CoA reductase, the rate limiting enzyme in cholesterol synthesis, was reduced in the SC GM of ALS patients. Increased cytosolic phospholipase A2 activity and lyso-phosphatidylcholine (Lyso-PC) levels in ALS patients suggests that CE accumulation was driven by acyl group transfer from phosphatidylcholine to cholesterol. Notably, Lyso-PC, a by-product of CE synthesis, was toxic to human MNs in vitro Elevations in CE, TAG, and Lyso-PC were also found in the SC of SOD1G93A mice, a model of ALS. Similar to ALS patients, a compensatory down regulation of cholesterol synthesis occurred in the SC of SOD1G93A mice; levels of sterol regulatory element binding protein 2 (SREBP2) - a transcriptional regulator of cholesterol synthesis, progressively declined. Remarkably, overexpressing SREBP2 in the SC of normal mice to model CE accumulation led to ALS-like lipid pathology, MN death, astrogliosis, paralysis, and reduced survival. Thus, SC lipid dysregulation in ALS likely contributes to neurodegeneration and developing therapies to restore lipid homeostasis may lead to a treatment for ALS.SIGNIFICANCE STATEMENTNeurons that control muscular function progressively degenerate in patients with amyotrophic lateral sclerosis (ALS). Lipid dysregulation is a feature of ALS; however, it is unclear if disrupted lipid homeostasis (i.e., lipid cacostasis) occurs proximal to degenerating neurons in the spinal cord, what causes it, and if it contributes to neurodegeneration. Here we show that lipid cacostasis occurs in the spinal cord grey matter of ALS patients. Lipid accumulation was not associated with an aberrant increase in synthesis or reduced hydrolysis, as enzymatic and transcriptional regulators of lipid synthesis were downregulated during disease. Lastly, we demonstrated that genetic induction of lipid cacostasis in the CNS of normal mice was associated with ALS-like lipid pathology, astrogliosis, neurodegeneration, and clinical features of ALS.