Inhibition of fatty acid amide hydrolase prevents pathology in neurovisceral acid sphingomyelinase deficiency by rescuing defective endocannabinoid signaling.
Inhibition of fatty acid amide hydrolase prevents pathology in neurovisceral acid sphingomyelinase deficiency by rescuing defective endocannabinoid signaling.
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DOI：
10.15252/emmm.201911776
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发表时间：
2020-11-06
影响因子：
11.1
通讯作者：
Ledesma MD
中科院分区：
文献类型：
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作者：
Bartoll A;Toledano-Zaragoza A;Casas J;Guzmán M;Schuchman EH;Ledesma MD
酸性鞘磷脂酶缺乏症 (ASMD) 会导致细胞内鞘磷脂 (SM) 积累、神经退行性变和过早死亡。在这里，我们描述了 ASM 敲除 (ASM-KO) 小鼠和 ASMD 患者神经元中内源性大麻素 (eCB) 系统的下调。高 SM 降低了神经元过程中 eCB 受体 CB 1 的表达并诱导其在溶酶体中的积累。通过抑制 eCB 降解酶脂肪酸酰胺水解酶 (FAAH) 激活 CB 1 受体信号，降低 ASM-KO 神经元中的 SM 水平。用 FAAH 抑制剂口服治疗 ASM-KO 小鼠可防止 SM 积聚；减轻炎症、神经退行性变和行为改变；并延长使用寿命。即使在疾病晚期单次给药后，这种治疗也显示出益处。我们还发现小鼠模型和另一种鞘脂贮积症 C 型尼曼-皮克病 (NPC) 患者的神经元中 CB 1 受体下调。我们展示了 FAAH 抑制可有效降低鼻咽癌患者来源的细胞和鼻咽癌小鼠模型大脑中的 SM 和胆固醇水平。我们的研究结果揭示了神经元 SM 和 eCB 系统之间的病理生理学串扰，并为 ASMD 和其他鞘脂沉积症提供了新的治疗方法。这项研究显示了两种溶酶体贮积症神经元内源性大麻素 (eCB) 系统的下调：酸性鞘磷脂酶缺乏症 (ASMD) 和尼曼皮克 C 型 (NPC)。 eCB 药理学增强可预防这些疾病小鼠模型的脑病理学。
Acid sphingomyelinase deficiency (ASMD) leads to cellular accumulation of sphingomyelin (SM), neurodegeneration, and early death. Here, we describe the downregulation of the endocannabinoid (eCB) system in neurons of ASM knockout (ASM‐KO) mice and a ASMD patient. High SM reduced expression of the eCB receptor CB 1 in neuronal processes and induced its accumulation in lysosomes. Activation of CB 1 receptor signaling, through inhibition of the eCB‐degrading enzyme fatty acid amide hydrolase (FAAH), reduced SM levels in ASM‐KO neurons. Oral treatment of ASM‐KO mice with a FAAH inhibitor prevented SM buildup; alleviated inflammation, neurodegeneration, and behavioral alterations; and extended lifespan. This treatment showed benefits even after a single administration at advanced disease stages. We also found CB 1 receptor downregulation in neurons of a mouse model and a patient of another sphingolipid storage disorder, Niemann–Pick disease type C (NPC). We showed the efficacy of FAAH inhibition to reduce SM and cholesterol levels in NPC patient‐derived cells and in the brain of a NPC mouse model. Our findings reveal a pathophysiological crosstalk between neuronal SM and the eCB system and offer a new treatment for ASMD and other sphingolipidoses. This study shows the downregulation of the endocannabinoid (eCB) system in neurons of two lysosomal storage disorders: acid sphingomyelinase deficiency (ASMD) and Niemann Pick type C (NPC). Brain pathology in mouse models of these diseases was prevented by eCB pharmacological enhancement.