Neutral Lipid Cacostasis Contributes to Disease Pathogenesis in Amyotrophic Lateral Sclerosis
Neutral Lipid Cacostasis Contributes to Disease Pathogenesis in Amyotrophic Lateral Sclerosis
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DOI：
10.1523/jneurosci.1388-20.2020
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发表时间：
2020-11-18
影响因子：
5.3
通讯作者：
Shihabuddin, Lamya S.
中科院分区：
文献类型：
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作者：
Dodge, James C.;Jensen, Elizabeth H.;Shihabuddin, Lamya S.
肌萎缩侧索硬化症（Amyotrophic lateral sclerosis，ALS）是一种以运动神经元（motor neuron，MN）死亡为特征的致死性神经肌肉疾病。脂质调节障碍在疾病期间表现出来;然而，目前尚不清楚脂质稳态是否在脊髓灰质（GM）中受到不利影响，如果是这样，是否是因为脂质合成异常增加。此外，尚不清楚脂质失调是否有助于MN死亡。在这里，我们表明，胆固醇酯（CE）和三酰甘油水平升高几倍，在脊髓GM的男性散发性ALS患者。有趣的是，HMG-CoA还原酶（胆固醇合成中的限速酶）在ALS患者的脊髓GM中减少。ALS患者胞浆磷脂酶A2活性和溶血磷脂酰胆碱（Lyso-PC）水平的增加表明，CE蓄积是由PC向胆固醇的酰基转移驱动的。值得注意的是，Lyso-PC，CE合成的副产物，在体外对人MN有毒。在ALS模型SOD 1（G93 A）小鼠的脊髓中也发现CE、三酰甘油和Lyso-PC升高。与ALS患者相似，SOD 1（G93 A）小鼠脊髓中发生了胆固醇合成的代偿性下调;固醇调节元件结合蛋白2（胆固醇合成的转录调节因子）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积累导致ALS样脂质病理学、MN死亡、星形胶质细胞增生、瘫痪和存活率降低。因此，ALS中的脊髓脂质失调可能有助于神经变性，并且开发恢复脂质稳态的疗法可能导致ALS的治疗。
Amyotrophic lateral sclerosis (ALS) is a fatal neuromuscular disease characterized by motor neuron (MN) death. Lipid dysre-gulation 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.