Amyotrophic lateral sclerosis (ALS) is a fatal neuromuscular disease characterized by motor neuron (MN) death. Lipid dysregulation manifests during disease; however, it is unclear whether lipid homeostasis is adversely affected in the in the spinal cord gray matter (GM), and if so, whether it is because of an aberrant increase in lipid synthesis. Moreover, it is unknown whether lipid dysregulation contributes to MN death. Here, we show that cholesterol ester (CE) and triacylglycerol levels are elevated several-fold in the spinal cord GM of male sporadic ALS patients. Interestingly, HMG-CoA reductase, the rate-limiting enzyme in cholesterol synthesis, was reduced in the spinal cord GM of ALS patients. Increased cytosolic phospholipase A2 activity and lyso-phosphatidylcholine (Lyso-PC) levels in ALS patients suggest that CE accumulation was driven by acyl group transfer from PC to cholesterol. Notably, Lyso-PC, a byproduct of CE synthesis, was toxic to human MNs in vitro. Elevations in CE, triacylglycerol, and Lyso-PC were also found in the spinal cord of SOD1^G93A mice, a model of ALS. Similar to ALS patients, a compensatory downregulation of cholesterol synthesis occurred in the spinal cord of SOD1^G93A mice; levels of sterol regulatory element binding protein 2, a transcriptional regulator of cholesterol synthesis, progressively declined. Remarkably, overexpressing sterol regulatory element binding protein 2 in the spinal cord of normal mice to model CE accumulation led to ALS-like lipid pathology, MN death, astrogliosis, paralysis, and reduced survival. Thus, spinal cord lipid dysregulation in ALS likely contributes to neurodegeneration and developing therapies to restore lipid homeostasis may lead to a treatment for ALS.

SIGNIFICANCE STATEMENT Neurons that control muscular function progressively degenerate in patients with amyotrophic lateral sclerosis (ALS). Lipid dysregulation is a feature of ALS; however, it is unclear whether disrupted lipid homeostasis (i.e., lipid cacostasis) occurs proximal to degenerating neurons in the spinal cord, what causes it, and whether it contributes to neurodegeneration. Here we show that lipid cacostasis occurs in the spinal cord gray 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. Last, 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.

肌萎缩性侧索硬化症（ALS）是一种致命的神经肌肉疾病，其特征在于运动神经元（MN）死亡。疾病期间血脂异常。但是，尚不清楚脂质稳态在脊髓灰质（GM）中是否受到不利影响，如果存在，是否是由于脂质合成异常增加所致。此外，尚不清楚脂质失调是否导致MN死亡。在这里，我们显示男性散发性ALS患者的脊髓GM中胆固醇酯（CE）和三酰基甘油水平提高了几倍。有趣的是，ALS患者的脊髓GM中HMG-CoA还原酶是胆固醇合成中的限速酶。ALS患者的胞质磷脂酶A2活性和溶血磷脂酰胆碱（Lyso-PC）水平升高，表明CE积累是由酰基从PC转移到胆固醇驱动的。值得注意的是，CE合成的副产物Lyso-PC对人类MN有毒体外。在ALS的模型SOD1 ^G93A小鼠的脊髓中也发现了CE，三酰甘油和Lyso-PC的升高。与ALS患者类似，SOD1 ^G93A小鼠的脊髓中胆固醇合成的代偿性下调。胆固醇合成的转录调节因子，固醇调节元件结合蛋白2的水平逐渐下降。值得注意的是，在正常小鼠的脊髓中过表达固醇调节元件结合蛋白2以模拟CE累积可导致ALS类脂质病理，MN死亡，星形胶质细胞增多症，瘫痪和存活率降低。因此，ALS中的脊髓脂质失调可能导致神经退行性变，开发恢复脂质稳态的疗法可能会导致ALS的治疗。

重要性声明在肌萎缩性侧索硬化症（ALS）患者中，控制肌肉功能的神经元逐渐退化。脂质失调是ALS的特征。然而，尚不清楚破坏的脂质稳态（即脂质代谢）是否发生在脊髓中退化的神经元的近端，其原因是什么，以及它是否有助于神经退行性变。在这里，我们显示脂质卡斯塔西斯病发生在ALS患者的脊髓灰质中。脂质蓄积与合成异常增加或水解减少无关，因为疾病期间脂质合成的酶和转录调节因子被下调。最后，我们证明了正常小鼠中枢神经系统中脂质卡斯塔西斯的遗传诱导与ALS样脂质病理学，星形胶质变，神经退行性变以及ALS的临床特征有关。